Heterocyclic carboxamide-containing thiourea inhibitors of herpes viruses containing phenylenediamine group

ABSTRACT

Compounds having the formula:                    
     are provided which are useful in the treatment of diseases associated with herpes viruses.

This application claims the benefit of U.S. Provisional Application Nos.60/150,698, 60/155,240, 60/228,808, 60/228,805, 60/155,192, 60/150,692,60/228,809 each of which was filed Dec. 9, 1998. These applications areherein incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

Eight viruses have been identified which are members of the familyHerpesviridae (reviewed in Roizman, B. 1996. Herpesviridae, p.2221-2230. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), FieldsVirology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.). Eachmember of this family is characterized by an enveloped virus containingproteinaceous tegument and nucleocapsid, the latter of which houses theviruses' relatively large double-stranded DNA genome (i.e. approximately80-250 kilobases). Members of the human alphaherpesvirus subfamily areneurotropic and include herpes simplex virus type 1 (HSV-1) and type 2(HSV-2), and varicella-zoster virus (VZV). The human betaherpesvirusesare cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and humanherpesvirus 7 (HHV-7). The gammaherpesviruses are lymphotropic andinclude Epstein-Barr virus (EBV) and Kaposi's herpesvirus (HHV-8). Eachof these herpesviruses is causally-related to human disease, includingherpes labialis and herpes genitalis (HSV-1 and HSV-2 [Whitley, R. J.1996. Herpes Simplex Viruses, p. 2297-2342. In B. N. Fields, D. M.Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-RavenPublishers, Philadelphia, Pa.]); chicken pox and shingles (VZV [Arvin,A. 1996. Varicella-Zoster Virus, p. 2547-2585. In B. N. Fields, D. M.Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-RavenPublishers, Philadelphia, Pa.]); infectious mononucleosis (EBV[Rickinson, A. B. and Kieff, E. 1996. Epstein-Barr Virus, p. 2397-2446.In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology,3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]); pneumonia andretinitis (HCMV [(Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus,p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.),Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia,Pa.]); exanthem subitum (HHV-6 [(Pellet, P. E, and Black, J. B. 1996.Human Herpesvirus 6, p. 2587-2608. In B. N. Fields, D. M. Knipe, and P.M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers,Philadelphia, Pa.]); and HHV-7 [Frenkel, N., and Roffman, E. 1996. HumanHerpesvirus 7, p. 2609-2622. In B. N. Fields, D. M. Knipe, and P. M.Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers,Philadelphia, Pa.]); and Kaposi's sarcoma (HHV-8 [Neipel, F., Albrecht,J. C., and Fleckenstein, B. 1997. Cell-homologous genes in the Kaposi'ssarcoma-associated rhadinovirus human herpesvirus 8: determinants of itspathogenicity? J. Virol. 71:4187-92, 1997]). HCMV is considered in moredetail below. Following the primary infection, herpesviruses establishlatency within the infected individual and remain there for theremainder of his/her life. Periodic reactivation of latent virus isclinically relevant. In the case of HSV, reactivated virus can betransmitted to infants during birth, causing either skin or eyeinfection, central nervous system infection, or disseminated infection(i.e. multiple organs or systems). Shingles is the clinicalmanifestation of VZV reactivation. Treatment of HSV and VZV is generallywith antiviral drugs such as acyclovir (Glaxo Wellcome), ganciclovir(Roche) and foscarnet (Asta) which target viral encoded DNA polymerase.

HCMV is a ubiquitous opportunistic pathogen infecting 50-90% of theadult population (Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus,p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.),Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia,Pa.). Primary infection with HCMV is usually asymptomatic, althoughheterophile negative mononucleosis has been observed. The virus ishorizontally transmitted by sexual contact, breast milk, and saliva.Intrauterine transmission of HCMV from the pregnant mother to the fetusoccurs and is often the cause of serious clinical consequences. HCMVremains in a latent state within the infected person for the remainderof his/her life. Cell-mediated immunity plays a central role incontrolling reactivation from latency. Impaired cellular immunity leadsto reactivation of latent HCMV in seropositive persons.

HCMV disease is associated with deficient or immature cellular immunity.There are 3 major categories of persons with HCMV disease (reviewed byBritt and Alford, 1996). (1) In immunocompromised (AIDS) patients, HCMVis one of the two most common pathogens causing clinical disease (theother is Pneumocystis). The most common manifestation of HCMV in AIDS isretinitis, although infection of other organs including the adrenalglands, lungs, GI tract, and central nervous system are also reportedfrequently. 90% of AIDs patients have active HCMV infection; 25-40%(−85,000 patients in the United States) have life- or sight-threateningHCMV disease. HCMV is the cause of death in 10% of persons with AIDs.(2) Due to immune system suppression to reduce the risk of graftrejection, HCMV reactivation or reinfection is common amongst kidney,liver, heart, and allogeneic bone marrow transplant patients. Pneumoniais the most common HCMV disease in these patients, occurring in up to70% of these transplant patients. (3) Congenital infection due to HCMVoccurs in 1% of all births, about 40K per year. Up to 25% of theseinfants are symptomatic for HCMV disease between ages 0-3 years. HCMVdisease is progressive, causing mental retardation and neurologicalabnormalities, in children. Recent studies suggest that treatment withanti-HCMV drugs may reduce morbidity in these children.

Several antiviral drugs are currently being marketed (Bron, D., R.Snoeck, and L. Lagneaux. 1996. New insights into the pathogenesis andtreatment of cytomegalovirus. Exp. Opin. Invest. Drugs 5:337-344;Crumpacker, C. 1996. Ganciclovir. New Eng. J. Med. 335:721-729; Sachs,S., and F. Alrabiah. 1996. Novel herpes treatments: a review. Exp. Opin.Invest. Drugs 5:169-183). These include: ganciclovir (Roche), anucleoside analog with hemopoietic cell toxicity; foscarnet (Astra), apyrophosphate analog with nephrotoxicity; and cidofovir, Gilead), anucleoside phosphonate with acute nephrotoxicity. Each of these drugstarget the viral-encoded DNA polymerase, are typically administeredintravenously due to their low bioavailability, and, as noted above, arethe source of significant toxicity. Ganciclovir-resistant mutants whicharise clinically are often cross-resistant with cidofovir. Hence, thereis a need for safer (i.e. less toxic), orally bioavailable anti-viraldrugs which are directed against novel viral targets.

Phenyl thioureas are disclosed for use in a variety of pharmaceuticalapplications. Armistead, et al., WO 97/40028, teaches phenyl ureas andthioureas as inhibitors of the inosine monophosphate dehydrogenase(IMPDH) enzyme which is taught to play a role in viral replicationdiseases such herpes.

Widdowson, et al., WO 96/25157, teaches phenyl urea and thioureacompounds of the below formula for treating diseases mediated by thechemokine, interleukin-8.

Morin, Jr., et al., U.S. Pat. No. 5,593,993 teaches certain phenylthiourea compounds for treatment of AIDs and the inhibition of thereplication of HIV and related viruses.

Therefore, it is an object of this invention to provide compounds, andpharmaceutically acceptable salts thereof, to inhibit and/or treatdiseases associated with herpes viruses including human cytomegalovirus,herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus,human herpesviruses-6 and -7, and Kaposi herpesvirus.

DESCRIPTION OF THE INVENTION

In accordance with the present invention are provided compounds havingthe formula:

wherein

R₁-R₅ are independently selected from hydrogen, alkyl of 1 to 6 carbonatoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms,perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms,heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen,—CN, —NO₂, —CO₂R₆, —COR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, —CONR₇R₈,—NR₆N(R₇R₈), —N(R₇R₈) or W—Y—(CH₂)_(n)— Z provided that at least one ofR₁-R₅ is not hydrogen; or R₂ and R₃ or R₃ and R₄, taken together form a3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl;

R₆ and R₇ are independently hydrogen, alkyl of 1 to 6 carbon atoms,perhaloalkyl of 1 to 6 carbon atoms, or aryl;

R₈ is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3to 10 members, aryl or heteroaryl, or

R₇ and R₈, taken together may form a 3 to 7 membered heterocycloalkyl;

W is O, NR₆, or is absent;

Y is —(CO)— or —(CO₂)—, or is absent;

Z is alkyl of 1 to 4 carbon atoms, —CN, —CO₂R₆, COR₆, —CONR₇R₈, —OCOR₆,—NR₆COR₇, —OCONR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, SR₆N(R₇R₈), —N(R₇R₈) orphenyl;

G is monocyclic heteroaryl;

X is a bond, —NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms,alkylamino of 1 to 6 carbon atoms, or (CH)J;

J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms,phenyl or benzyl; and

n is an integer from 1 to 6, or pharmaceutical salts thereof.

In some preferred embodiments of the present invention, R₁-R₅ areindependently, hydrogen alkyl of 1 to 6 carbon atoms, halogen,perhaloalkyl of 1 to 6 carbon atoms, OR₆ or N(R₇R₈). Preferably, 1 to 3of R₁-R₅ is not hydrogen. Most preferably, 2 of R₁-R₅ is not hydrogen.In preferred compounds of the present invention R₃ and R₅, or R₄ and R₅are preferably, independently, halogen or CF₃.

In some embodiments of the present invention G is monocyclic heteroaryl,preferably thiazolyl, thiadiazolyl, oxazolyl or furyl. G is preferablynot substituted.

In some embodiments of the present invention X is a bond, CH(J) or C₁-C₄alkyl. Preferably, when X is C₁-C₄ alkyl, said alkyl is straight chainalkyl. When X is CH(J), J is preferably methyl.

Preferred compounds of the present invention are the following compoundswhich include pharmaceutical salts thereof.

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-piperidin-1-yl-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-dimethylamino-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-fluoro-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiazole-4-carboxylic acid{4-[3-(4-tert-butyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-dichloro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-chloro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-tert-butyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-5-trifluoromethyl-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2,4-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-fluoro-3-trifluoromethyl-phenyl)ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-iodo-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2,4-dichloro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-5-trifluoromethyl-phenoxy)-ethyl]-thioureido}-phenyl)-amide,

Thiazole-4-carboxylic acid{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-iodo-phenyl)-ethyl]-thioureido}-phenyl)-amide,

Furan-2-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(2-methyl-butyl)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-isobutyl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-dimethylamino-5-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-chloro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide,

Thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide,

Thiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-dichloro-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-iodo-phenyl)-thioureido]-phenyl}-amide,

Furan-2-carboxylic acid[4-(3-benzo[1,3]dioxol-5-ylmethyl-thioureido)-phenyl]-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,3-diphenyl-propyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-fluoro-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-bromo-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(butyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dimethyl-benzyl)-thioureido]-phenyl}-amide,

Thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-bromo-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-chloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-ethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-phenoxy)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-difluoro-benzyl)-thioureido]-phenyl}-amide,

Furan-2-carboxylicacid{4-[3-(3,5-dichloro-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-p-tolyl-ethyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-phenyl-butyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-iodo-benzyl)-thioureido]-phenyl}-amide,

Furan-2-carboxylic acid(4-{3-[2-(3-bromo-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide,

Oxazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-difluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,5-difluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-amino-5-chloro-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-bromo-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(isobutyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylicacid{4-[3-(3-phenyl-propyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylicacid{4-[3-(3-chloro-4-fluoro-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylicacid{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-amide,

Furan-2-carboxylic acid{4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-morpholin-4-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-fluoro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-fluoro-phenoxy)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-iodo-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-bromo-4-trifluoromethoxy-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-dimethylamino-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-benzyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-difluoro-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl}-amide,

Furan-2-carboxylic acid{4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-nitro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-piperidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

Oxazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide,

Furan-2-carboxylic acid{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-benzo[1,3]dioxol-5-ylmethyl-thioureido)-phenyl]-amide,

[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-phenethyl-thioureido)-phenyl]-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-chloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylicacid(4-{3-[3-chloro-4-(1H-pyrazol-3-yl)-phenyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(2-piperidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-amide,

Furan-2-carboxylic acid [4-(3-benzyl-thioureido)-phenyl]-amide,

Furan-2-carboxylic acid(4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide,

Furan-2-carboxylic acid{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-chloro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

Oxazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,

Furan-2-carboxylic acid(4-{3-[2-(3,4-dichloro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-chloro-benzyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-bromo-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-fluoro-benzyl)-thioureido]-phenyl}-amide,

Furan-2-carboxylic acid{4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-phenyl}-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[(1S)-1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[(1R)-1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(1S)-1-(4-chloro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[(1R)-1-(4-chloro-phenyl)-ethyl]-thioureido}-phenyl)-amide,

N-[4-[[[[1-(4—Cyanophenyl)ethyl]amino]thioxomethyl]amino]phenyl]-1,2,3-thiadiazole-4-carboxamide,

Thiazole-4-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide,

[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-(1S)-[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide,

N-(4-{[({1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide,

N-(4-{[({1-[4-chloro-3-hiadiazole-4-carboxamide,

N-(4-{[({1S)-1-[3,5-thiazole-4-carboxamide,

N-(4-{[({1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,

N-(4-{[({1-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,

N-(4-{[({1-[2-fluoro-5-trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,

N-(4-{[({1-[2,4-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(2,4-dimethylphenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(2,4-dichlorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(3-methylphenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(2-chloro-4-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl)-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(3,4-difluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(4-bromo-2-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(3-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(2-bromophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(3-bromophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-(4-{[({1-[2-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(2,4-difluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-(4-{[({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl)amino)carbothioyl]amino)phenyl)-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(3,4-dichlorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-(4-{[({1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,

N-(4-{[({1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(4-chloro-2-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-(4-{[({1-[4-fluoro-2-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl}amino}phenyl)-1,3-thiazole-4-carboxamide,

N-4-{[({[1-(4-chloro-3-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl)-1,3-thiazole-4-carboxamide,

N-(4-[({[1-(2-bromo-4-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(3,4-dibromophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,

N-{4-[({[1-(3-chloro-4-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl)-1,3-thiazole-4-carboxamide,

N-(4-([(1-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide,

N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]butyl}amino)carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide,

N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]pentyl}amino)carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide,

N-{4-[({[[3,5-bis(trifluoromethyl)phenyl](phenyl)methyl)amino)carbothioyl)amino]phenyl}-1,2,3-thiadiazole-4-carboxamide,

N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl)-1-methylethyl}amino)carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide,

N-(4-{[({[3,5-bis(trifluoromethyl)benzyl]amino}carbothioyl)amino]phenyl}-1H-imidazole-4-carboxamide,

N-{4-[({([1-(4-fluorophenyl)ethyl)amino}carbothioyl)amino]phenyl}-1H-imidazole-4-carboxamide,

N-{4-[({[3,5-bis(trifluoromethyl)benzyl]amino}carbothioyl)amino]phenyl}-1-methyl-1H-imidazole-4-carboxamide,

N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide;and

pharmaceutical salts thereof.

Unless otherwise defined, the terms used herein have the followingmeanings.

Alkyl as used herein refers to straight or branched chain lower alkyl of1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

Alkenyl as used herein refers to straight or branched chain lower alkylof 2 to 6 carbon atoms containing at least one carbon-carbon doublebond. Alkenyl includes vinyl groups.

Alkynyl as used herein refers to straight or branched chain lower alkylof 2 to 6 carbon atoms containing at least one carbon-carbon triplebond.

Alkyl, alkenyl and alkynyl groups of the present invention may besubstituted or unsubstituted.

Cycloalkyl refers to a saturated mono or bicyclic ring system of 3 to 10carbon atoms. Exemplary cycloalkyl groups include cyclopentyl,cyclohexyl and cycloheptyl. Cycloalkyl groups of the present inventionmay be substituted or unsubstituted.

Heterocycloalkyl refers to a saturated mono or bicyclic ring system of 3to 10 members having 1 to 3 heteroatoms selected from N, S and O,including, but not limited to aziridinyl, azetidinyl, imidazolidinyl,morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, piperidinyl,and pyrrolidinyl. Heterocycloalkyl groups of the present invention maybe substituted or unsubstituted.

Aryl, as used herein refers to an aromatic mono or bicyclic ring of 6 to10 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, andbiphenyl. Aryl groups of the present invention may be substituted orunsubstituted.

Heteroaryl as used herein refers to an aromatic mono or bicyclic ring of5 to 10 members having 1 to 3 heteroatoms selected from N, S or Oincluding, but not limited to thiazolyl, thiadiazolyl, oxazolyl, furyl,indolyl, benzothiazolyl, benzotriazolyl, benzodioxyl, indazolyl, andbenzofuryl. Preferred heteroaryls include quinolyl, isoquinolyl,napthalenyl, benzofuranyl, benzothienyl, indolyl, pyridyl, pyrazinyl,thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl,pyrazolyl, triazolyl, thiadiazolyl, and imidazolyl. Heteroaryl groups ofthe present invention may be substituted or unsubstituted.

Perhaloalkyl refers to an alkyl group of 1 to 6 carbon atoms in whichthree or more hydrogens are substituted with halogen.

Phenyl as used herein refers to a 6 membered aromatic ring.

Halogen, as used herein refers to chlorine, bromine, iodine andfluorine.

Unless otherwise limited, substitutents are unsubstituted and mayinclude alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms,heterocycloalkyl of 1 to 6 members, perhaloalkyl of 1 to 6 carbon atoms,amino, azido, hydroxy, alkylamino, dialkylamino, aryl or heteroaryl.

Carbon number refers to the number of carbons in the carbon backbone anddoes not include carbon atoms occurring in substituents such as an alkylor alkoxy substituents.

Where terms are used in combination, the definition for each individualpart of the combination applies unless defined otherwise. For instance,alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyl andcycloalkyl are as previously described.

Pharmaceutically acceptable salts are the acid addition salts which canbe formed from a compound of the above general formula and apharmaceutically acceptable acid such as phosphoric, sulfuric,hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic,lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, andthe like.

The compounds of this invention contain a chiral center, providing forvarious seteroisomeric forms of the compounds such as racemic mixturesas well as the individual optical isomers. In some preferred embodimentsof the present invention the compounds of the present invention aresubstantially pure optical isomers. By substantially pure optical isomeris meant the composition contains greater than 75% of the desired isomerand may include no more than 25% of the undesired isomer. In morepreferred embodiments the pure optical isomer is greater than 90% of thedesired isomer. The individual isomers can be prepared directly or byasymmetric or stereospecific synthesis or by conventional separation ofoptical isomers from the racemic mixture.

Compounds of the present invention may be prepared by those skilled inthe art of organic synthesis employing methods described below whichutilize readily available reagents and starting materials unlessotherwise described. Compounds of the present invention are thusprepared in accordance with the following schemes.

The novel compounds of the present invention are prepared according tothe following reaction schemes.

Referring to Methods 31 and 34, reacting appropriately substitutedamines 2, wherein the substitutents R₁-R₅, and X are described as above,with appropriately substituted isothiocyanates 3, wherein thesubstituent G is described above, either neat or in an appropriatesolvent such as tetrahydrofuran, acetonitrile, ethyl acetate,dichloromethane, or N,N-dimethylformamide affords the desiredthioureas 1. Similarly, reaction of appropriately substitutedisothiocyanates 4, wherein the substitutents R₁-R₅, and X are describedas above with appropriately substituted anilines 5, wherein thesubstituent G is described above, in a convenient solvent such as thoselisted above affords the desired thioureas 1.

Alternatively, appropriately substituted thioureas 1 can be prepared asdescribed by Methods 32 and 33 by reacting anilines 2 and 5, whereinR₁-R₅, and G are described as above, in the presence of either one molarequivalent of 1,1′-thiocarbonyldiimidazole or 1,1′-carbonyldiimidazolein an appropriate solvent such as dichloromethane and tetrahydrofuran ormixtures thereof or one molar equivalent of1,1′-thiocarbonyl-di-(1,2,4)-triazole or1,1′-carbonyl-di-(1,2,4)-triazole in an appropriate solvent such asdichloromethane and tetrahydrofuran or mixtures thereof at roomtemperature.

In certain instances, subsequent chemical modification of the finalthioureas 1 was required. These methods, Methods 35-39, are summarizedbelow.

Thioureas 1 wherein at least one substituent of R₁-R₅ is 1-hydroxyethoxyor carboxy-methoxy, G is defined as above and X equals a bond, may beprepared from the corresponding alkyl esters by alkaline hydrolysis withaqueous sodium or potassium hydroxide in a suitable solvent such asmethanol, tetrahydrofuran or mixtures thereof at room temperature inaccordance with Methods 35 and 36.

Thioureas 1 wherein at least one substituent of R₁-R₅ is 1-acyloxyethoxyor methansulfonoxyethoxy, G is defined as above and X equals a bond, maybe prepared from the corresponding 1-hydroxyethoxy derivative byacylation with appropriate acylating agents such as benzoic acidchloride or methanesulfonic acid chloride in the presence of a suitabletertiary amine base such as triethylamine or diisopropylethylamine in asuitable solvent such as dichloromethane or the like at room temperaturein accordance with Methods 37 and 38.

Thioureas 1 wherein at least one substituent of R₁-R₅ is 1-aminoethoxy,G is defined as above and X equals a bond, may be prepared from thecorresponding 1-methanesulfonoxy-ethoxy derivative by reaction with anappropriate secondary amine such as dimethylamine in a suitable solventmixture such as tetrahydrofuran and water or the like at roomtemperature in accordance with Method 39.

Thioureas 1 wherein at least one substituent of R₁-R₅ is 1-aminoalkyl, Gis defined as above and X equals a bond, may be prepared from thecorresponding 1-azidoalkyl derivative by reaction with stannous chloridein a suitable solvent such as methanol, ethanol or the like at roomtemperature in accordance with Method 40.

The intermediate isothiocyanates 3 and 4 shown above in Methods 31 and34 are prepared in accordance with Method 41 (below) essentiallyaccording to the procedures of Staab, H. A. and Walther, G. JustusLiebigs Ann. Chem. 657, 104 (1962)) by reacting appropriatelysubstituted amines 5 or 2, respectively, wherein R₁-R₅ and G aredescribed above and X is defined above, with one molar equivalent of1,1′-thiocarbonyldiimidazole in an appropriate solvent such asdichloromethane and tetrahydrofuran or mixtures thereof.

The intermediates 2 and 5 may be prepared according to the followingprotocols:

According to Methods 1A-1G, amines 2, wherein R₁-R₅ are defined aboveand X is defined above, amines 5 may be prepared by reduction of theappropriately substituted nitrobenzenes according to a variety ofprocedures known to those skilled in the art and described in R. J.Lindsay, Comprehensive Organic Chemistry (ed. Sutherland), Volume 2,Chapter 6.3.1, Aromatic Amines, 1979. Such procedures include thereduction of nitrobenzenes to form anilines upon exposure to:

a) iron powder and a strong acid, such as hydrochloric acid (Methods 1A)either neat or in alcohol solvent such as methanol or ethanol, attemperatures ranging from room temperature to the refluxing temperatureof the solvent, or;

b) iron powder and glacial acetic acid (Method 1B), either neat or inalcohol solvent such as methanol or ethanol, at temperatures rangingfrom room temperature to the refluxing temperature of the solvent, or;

c) iron powder and aqueous ammonium chloride (Method 1C), either neat orin alcohol solvent such as methanol or ethanol, at temperatures rangingfrom room temperature to the refluxing temperature of the solvent, or;

d) tin and a strong mineral acid, such as hydrochloric acid (Method 1D),either neat or in alcohol solvent such as methanol or ethanol, attemperatures ranging from room temperature to the refluxing temperatureof the solvent, or;

e) when R₁-R₅ are selected from Cl, Br, I, —(OSO₂)—CF₃, or—(OSO₂)-1-(4-methylphenyl), by catalytic reduction such as with hydrogenand palladium on carbon (Method 1E) in an appropriate solvent such asmethanol, ethanol, or ethyl acetate, under one or more atmospheres ofpressure or;

f) when R₁-R₅ and R₉-R₁₂ are selected from Cl, Br, I, —(OSO₂)—CF₃ or—(OSO2)-1-(4-methylphenyl), by catalytic reduction such as withcyclohexene and palladium on carbon (Method 1F) in an appropriatesolvent such as methanol or ethanol, at temperatures ranging from roomtemperature to the refluxing temperature of the solvent, or;

g) aqueous sodium hydrosulfite in alcohol solvent at temperaturesranging from room temperature to the refluxing temperature of thesolvent (Method 1G).

Alternatively, according to Methods 3A-3C, amines 2, wherein R₁-R₅ aredefined above and X is defined above and anilines 5, above may beprepared by the cleavage of the aniline nitrogen-carbon bond of amideand carbamate derivatives of these anilines according to a variety ofprocedures known to those skilled in the art and described in Greene,Protective Groups in Organic Synthesis volume 2, Chapter 7, 1991, andreferences therein. Such procedures include:

a) the exposure of appropriately substitutedarylamino-tert-butyl-carbamates to a strong acid such as trifluoroaceticacid (Method 3A)either neat or in an appropriate solvent such asdichloromethane at temperatures between 0° C. and room temperature, or;

b) the exposure of appropriately substitutedarylamino-(2-trimethylsilylethyl)-carbamates to a fluoride ion sourcesuch as tetrabutylammonium fluoride or potassium fluoride (Method 3B) inaqueous acetonitrile or tetrahydrofuran or mixtures thereof attemperatures ranging from room temperature to the reflux temperature ofthe solvent, or;

c) the exposure of appropriately substitutedarylamino-trifluoroacetamides to a strong base such as sodium orpotassium hydroxide or sodium or potassium carbonate in an alcoholsolvent such as methanol or ethanol (Method 3C) at temperatures rangingfrom room temperature to the reflux temperature of the solvent.

Alternatively, according to Method 11, amines 2, wherein R₁-R₅ aredefined above, and X is defined above at least one substituent of R₁-R₅is defined as vinyl, may be prepared by the palladium catalyzed couplingof a vinyl trialkyltin reagent, such as tributylvinyltin, with anappropriately substituted bromo- or iodo-aniline, for example3-chloro-4-iodo-aniline, employing a palladium catalyst, such astris(dibenzylidineacetone)-bipalladium, and a ligand, such astriphenylarsine, in a suitable solvent such as tetrahydrofuran orN-methylpyrrolidinone, at temperatures ranging from room temperature tothe reflux temperature of the solvent, essentially according to theprocedures of V. Farina and G. P. Roth in Advances in Metal-OrganicChemistry, Vol. 5, 1-53, 1996 and references therein.

Alternatively, according to Method 42, amines 2, wherein R₁-R₅ aredefined above and X is defined above and at least one substituent of R₂or R₄ is defined as dialkylamino, may be prepared by the palladiumcatalyzed amination of an appropriately substituted 3- or 5-bromo- oriodo-aniline, for example 3-amino-5-bromobenzotrifluoride, by secondaryamines under conditions which employ a palladium catalyst, such asbis(dibenzylidineacetone)palladium, and a ligand, such astri-o-tolylphosphine, and at least two molar equivalents of a strongbase, such as lithium bis-(trimethylsilyl)amide in a sealed tube, in asuitable solvent such as tetrahydrofuran or toluene, at temperaturesranging from room temperature to 100° C., essentially according to theprocedures of J. F. Hartwig and J. Louie Tetrahedron Letters 36 (21),3609 (1995).

Alternatively, according to Method 43, amines 2, wherein R₁-R₅ aredefined above and X is defined above and at least one substituent of R₂or R₄ is defined as alkyl, may be prepared by the palladium catalyzedalkylation of an appropriately substituted 3- or 5-bromo-oriodo-aniline, for example 3-amino-5-bromobenzotrifluoride by alkenesunder conditions which employ a palladium catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride-dichloromethane complex and in the presence of9-borabicyclo[3.3.1] nonane and a suitable base such as aqueous sodiumhydroxide in a suitable solvent such as tetrahydrofuran or the like attemperatures ranging from room temperature to the reflux temperature ofthe solvent.

The acyl and carbamoyl amine derivatives utilized as starting materialsin Methods 3A-3C may be prepared by the derivatization of thecorresponding amines as described in Methods 2A-2G according to avariety of procedures known to those skilled in the art and described inGreene, Protective Groups in Organic Synthesis volume 2, Chapter 7,1991, and references therein. Such procedures include:

a) the reaction of an appropriately substituted amine withdi-tert-butyl-dicarbonate (Method 2A) in the presence or absence of oneor more molar equivalents of a tertiary amine such as triethylamine orN,N-diisopropylethylamine in a suitable solvent such as acetone,tetrahydrofuran, dimethylformamide, dichloromethane, and the like, attemperatures ranging from room temperature to the reflux temperature ofthe solvent to produce the corresponding arylamino-tert-butyl-carbamate,or;

b) the reaction of an appropriately substituted aniline with1-[2-(trimethylsilyl)ethoxycarbonyl-oxy]benzotriazole (Method 2B) in thepresence of a tertiary amine such as triethylamine ordiisopropylethylamine in a suitable solvent such as dimethylformamide atroom temperature to produce the correspondingarylamino-(2-trimethylsilylethyl)-carbamate, or;

c) the reaction of an appropriately substituted aniline with acarboxylic acid chloride or acid anhydride (Method 2C) either neat or inan appropriate solvent such as tetrahydrofuran, dimethylformamide,dichloromethane, pyridine and the like, in the presence of one or moremolar equivalents of a teriary amine base such as triethylamine orN,N-diisopropylethyl-amine to produce the corresponding arylaminoamide,or;

d) the reaction of an appropriately substituted nitro aniline with acarboxylic acid chloride (Method 2D) in the absence of one or more molarequivalents of a teriary amine base such as triethylamine orN,N-diisopropylethylamine either neat or in an appropriate solvent suchas tetrahydrofuran, 1,4-dioxane and the like at temperatures rangingfrom room temperature to the reflux temperature of the solvent toproduce the corresponding nitro arylaminoamide, or;

e) the reaction of an appropiately substituted aniline with a carboxylicacid (Method 2E) in the presence of a coupling agent such asbenzotriazole-1-yloxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate,2-(1H-benzotriazole-1-yloxy)-1,1,3,3-tetra-methyluroniumhexafluorophosphate, dicyclohexyl carbodiimide and the like and in thepresence of a tertiary amine such as triethylamine ordiisopropylethylamine in a suitable solvent such as diichloromethane,dimethylformamide and the like, at room temperature to produce thecorresponding arylaminoamide, or;

f) the reaction of an appropriately protected aniline such as anarylamino-tert-butyl-carbamate or the like in which at least onesubstituent of R₁-R₁₂ is defined as —W—Y—(CH₂)_(n)—Z wherein W, Y, and Zare defined as above, with a carboxylic acid anhydride (Method 2F) inthe presence of a suitable base such as pyridine in an appropriate suchas dichloromethane, dimethylformamide or the like at temperaturesranging from 0° C. to room temperature to produce the correspondingcarboxylic acid ester, or;

g) the reaction of an appropriately substituted aniline in which a tleast one substituent of R₁-R₅ is defined as hydroxyl withdi-tert-butyl-dicarbonate (Method 2G) in the absence of one or moremolar equivalents of a tertiary amine such as triethylamine orN,N-diisopropylethylamine in a suitable solvent such as acetone,tetrahydrofuran, dimethylformamide, dichloromethane, and the like, attemperatures ranging from room temperature to the reflux temperature ofthe solvent to produce the corresponding arylamino-tert-butyl-carbamate.

Nitrobenzene intermediates that are ultimately converted to amines 2 and5 by methods shown above in Methods 1A-1G may be prepared in accordancewith Methods 4A, 4C, 4E-4F.

Referring to Methods 4A, 4C, and 4E-4H, the nitrobenzene intermediateswhich are ultimately converted into amines 2, R₂ and R₄ are definedabove and R₁, R₃, and/or R₅ are defined as alkoxy, thioalkoxy,alkylsulfenyl, alkylsulfinyl, and dialkylamino may be prepared by thenucleophilic displacement of appropriately substituted 2-, 4-, and/or6-fluoro-, chloro-, bromo-, iodo-, trifluoromethylsulfonyl-, or(4-methylphenyl)sulfonyl-substituted nitrobenzenes by methods whichinclude the following:

a) reaction of alcohols with appropriately substituted 2- or 4- halo- orsulfonate esters of nitrobenzenes or benzonitriles (Method 4A) eitherneat or in an appropriate solvent such as tetrahydrofuran, dioxane,acetonitrile, N,N-dimethylformamide or dimethylsulfoxide in the presenceor absence of one or more molar equivalents of a base such as sodiumcarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide,sodium hydride, potassium hydride, or the like, at temperatures rangingfrom room temperature to the reflux temperature of the solvent;

b) reactions of preformed sodium, lithium, or potassium phenoxides withappropriately substituted 2- or 4- halo- or sulfonate esters ofnitrobenzenes or benzonitriles (Method 4H) either neat or in anappropriate solvent such as tetrahydrofuran, dioxane, acetonitrile,N,N-dimethylformamide or dimethylsulfoxide, at temperatures ranging fromroom temperature to the reflux temperature of the solvent, or;

c) reaction of ammonia, primary or secondary amines with appropriatelysubstituted 2- or 4-halo- or sulfonate esters of nitrobenzenes orbenzonitriles (Methods 4C,F) either neat or in an appropriate solventsuch as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethyl-formamideor dimethylsulfoxide, at temperatures ranging from room temperature tothe reflux temperature of the solvent;

d) reaction of preformed sodium, lithium, or potassium salts of amineswith appropriately substituted 2- or 4- halo- or sulfonate esters ofnitrobenzenes or benzonitriles (Method 4G) in an appropriate solventsuch as tetrahydrofuran at temperatures ranging from 0° C. to the refluxtemperature of the solvent, or;

e) reaction of sodium sulfide with appropriately substituted 2- or 4-halo- or sulfonate esters of nitrobenzenes or benzonitriles either neator in an appropriate solvent such as tetrahydro-furan, dioxane,acetonitrile, N,N-dimethylformamide or dimethylsulfoxide, attemperatures ranging from room temperature to the reflux temperature ofthe solvent, followed by the addition of an alkyl halide directly to thereaction mixture (Method 4E).

Alternatively, referring to Methods 5C and 6, the nitrobenzeneintermediates which are ultimately converted into amines 2, wherein atleast one substitutent R₁-R₅ is defined as alkoxy may be prepared fromthe corresponding substituted hydroxy-nitrobenzenes by methods whichinclude the following:

a) reaction of the hydroxy-nitrobenzene with an alkyl halide or dialkylsulfonate ester (Method 5C) in the presence of a base, such as potassiumcarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide,potassium hydride, or sodium hydride, in an appropriate solvent such asacetone, N,N-dimethylformamide, tetrahydrofuran or dimethylsulfoxide attemperatures ranging from room temperature to the reflux temperature ofthe solvent, or;

b) reaction of the hydroxy-nitrobenzene with an alkyl alcohol,triphenylphosphine, and a dialkylazadicarboxylate reagent (Method 6),such as diethylazodicarboxylate, in an anhydrous aprotic solvent such asdiethyl ether or tetrahydrofuran at temperatures ranging from 0° C. tothe reflux temperature of the solvent, essentially according to methodsdescribed in Mitsunobu, O, Synthesis 1981, 1 and references therein.

In addition, referring to Method 5A and 5E, the carbamoyl aminederivatives utilized as starting materials in Methods 3A-3C which areultimately converted into amines 2, wherein at least one substituentR₁-R₅ is defined as alkoxy may be prepared the corresponding substitutedhydroxy arylamino-tert-butyl-carbamate by reaction with alkyl halides,trifluormethane-sulfonates, 4-methylbenzenesulfonates, dialkylsulfonate,ethylene carbonate and the like in the presence of a suitable base suchas potassium carbonate in an appropriate solvent such as acetone,toluene, or N,N-dimethylformamide at temperatures ranging from roomtemperature to the reflux temperature of the solvent.

Alternatively, referring to Methods 7A-G, the nitrobenzene intermediateswhich are ultimately converted into amines 2, R₁ and/or R₃ is alkoxy,and R₂ and/or R₄ is a halogen, and X equals a bond, may be prepared bystandard halogenation reactions which include the following:

a) reaction of a 2- or 4- hydroxy-nitrobenzene with aqueous sodiumhypochlorite (Methods 7A and 7B), at room temperature or;

b) reaction of a 2-hydroxy-4-methoxy or 2,4-dimethoxynitrobenzene(Method 7C and 7D) with bromine in suitable solvent such as chloroform,dichlormethane, glacial acetic acid or the like in the presence or theabsence of silver trifluoroacetate at room temperature, or;

c) reaction of a 2,4-dimethoxynitrobenzene (Method 7E) withbenzyltrimethyl-ammonium dichloroiodate in the presence of anhydrouszinc chloride in a suitable solvent such as glacial acetic acid, at roomtemperature or;

d) reaction of a 2-hydroxy-4-methoxynitrobenzene (Method 7F) withbenzyltrimethyl-ammonium dichloroiodate in the presence of sodiumbicarbonate in a suitable solvent mixture such as dichloromethane andmethanol, at room temperature or;

e) reaction of a 2,4-dimethoxynitrobenzene (Method 7G) with3,5-dichloro-1-fluoropyridine triflate in a suitable solvent such astetrachloroethane, at a temperature ranging from room temperature to thereflux temperature of the solvent.

Referring to Method 8, the nitrobenzene intermediates which areultimately converted into amines 2, wherein R₄═—CF₃, and R₁-R₃ and R₅-R₈are defined as above and X equals a bond may be prepared from thecorresponding substituted 4-iodo-nitrobenzenes by reaction withtrimethyl(trifluoromethyl)silane in the presence of cuprous iodide andpotassium fluoride in a suitable solvent such as N,N-dimethylformamideor the like at a temperature ranging from room temperature to the refluxtemperature of the solvent in a sealed reaction vessel.

Referring to Methods 19A and 19B, the nitrobenzene intermediates whichare ultimately converted into amines 2, wherein R₄═—HNCOCH₂NR₇R₈ or—HNCOCH₂SR₆, and R₁-R₃ and R₅ are defined as above and X equals a bondmay be prepared from the corresponding substituted4-(N-chloroacetyl)-nitroaniline by reaction with either a suitablesecondary amine such as dimethylamine, morpholine or the like in asuitable solvent such as tetrahydrofuran and/or water mixtures attemperatures ranging from room temperature to the reflux temperature ofthe solvent or by reaction with an appropriate thiol in the presence ofa suitable base such as sodium or potassium carbonate or the like in asuitable solvent such as tetrahydrofuran, 1,4-dioxane or the like attemperatures ranging from room temperature to the reflux temperature ofthe solvent.

Referring to Method 25, the nitrobenzene intermediates which areultimately converted into amines 2, wherein at least one substituent ofR₁-R₅ is defined as triflate and X equals a bond may be prepared fromthe corresponding phenol by reaction with trifluoromethane-sulfonicanhydride in the presence of a tertiary amines such as triethylamine ordiisopropyl-ethylamine or the like in a suitable solvent such asdichloromethane at temperatures ranging from 0° C. to room temperature.

Referring to Methods 9, 9B, and 10, the carbamoyl amine derivativesutilized as starting materials in Methods 3A-3C which are ultimatelyconverted into amines 2, wherein at least one substituent R₁-R₅ isdefined as either alkylsulfenyl or alkylsulfinyl, may be prepared byreaction of the appropriate 4-alkylthio acyl-arylamino or carbamoylarylamino derivative with an appropriate oxidizing agent such asdimethyloxirane or sodium periodate in a suitable solvent mixture suchas acetone and dichloromethane or water at room temperature.

Referring to Method 12, the carbamoyl amine derivatives utilized asstarting materials in Methods 3A-3C which are ultimately converted intoamines 2, wherein R₄ is defined as 1-hydroxyethyl and R₁-R₃ and R₅ aredefined as above and X is a bond may be prepared by reacting thecorresponding 4-vinyl carbamoyl aniline with sodium borohydride in thepresence of mercuric acetate in a suitable solvent such astetrahydrofuran, 1,4-dioxane or the like and water at room temperature.

Referring to Method 13, the carbamoyl amine derivatives utilized asstarting materials in Methods 3A-3C which are ultimately converted intoamines 2, wherein R₄ is defined as 2-hydroxyethyl and R₁-R₃ and R₅ aredefined as above and X equals a bond, may be prepared by reacting thecorresponding 4-vinyl carbamoyl aniline with sodium borohydride in thepresence of glacial acetic acid in a suitable solvent such astetrahydrofuran, 1,4-dioxane or the like at temperatures ranging from 0°C. to room temperature.

Referring to Method 14, the carbamoyl amine derivatives utilized asstarting materials in Methods 3A-3C which are ultimately converted intoamines 2, wherein R₄ is defined as 1-azidoethyl and R₁-R₃ and R₅ aredefined as above and X is defined above, may be prepared by reacting thecorresponding 4-(1-hydroxyethyl) carbamoyl aniline with hydrazoic acidin the presence of a dialkylazodicarboxylate such asdiethylazodicarboxylate and triphenylphosphine in a suitable solventmixture such as tetrahydrofuran and dichloromethane at temperaturesranging from 0° C. to room temperature.

Referring to Method 15, the carbamoyl amine derivatives utilized asstarting materials in Methods 3A-3C which are ultimately converted intoamines 2, wherein R₄ is defined as 3-dimethylaminoprop-1-ynyl and R₁-R₃and R₅ are defined as above and X is defined above, may be prepared byreacting the corresponding 4-iodocarbamoyl aniline with1-dimethylamino-2-propyne in a suitable tertiary amine solvent such astriethylamine or diisopropylethylamine in the presence ofbis(triphenylphosphine)-palladium(II) chloride and cuprous iodide attemperatures ranging from room temperature to the reflux temperature ofthe solvent.

Referring to Method 16, the carbamoyl amine derivatives utilized asstarting materials in Methods 3A-3C which are ultimately converted intoamines 2, wherein R₄ is defined as 3-dimethylaminoacryloyl and R₁-R₃ andR₅ are defined as above and X equals a bond, may be prepared by reactingthe corresponding 4-(3-dimethylaminoprop-1-ynyl)carbamoyl aniline with asuitable peracid such as 3-chloroperoxybenzoic acid in a suitablesolvent mixture such as dichloromethane and methanol at temperaturesranging from 0° C. to room temperature.

Referring to Methods 17 and 18, the carbamoyl amine derivatives utilizedas starting materials in Methods 3A-3C which are ultimately convertedinto amines 2, wherein R₄ is defined as either 4-isoxazol-5-yl or4-(1H-pyrazol-3-yl) and R₁-R₃ and R₅ are defined as above and X equals abond, may be prepared by reacting the corresponding4-(3-dimethylamino-acryloyl)carbamoyl aniline with either hydroxylaminehydrochloride or hydrazine hydrate in a suitable solvent such as1,4-dioxane or ethanol and the like at room temperature.

Referring to Method 20, the carbamoyl amine derivatives utilized asstarting materials in Methods 3A-3C which are ultimately converted intoamines 2, wherein R₄═—HNCO₂Z, and R₁-R₃, R₅, and Z are defined as aboveand X equals a bond, may be prepared by reacting the corresponding4-aminocarbamoyl aniline with 1,1-carbonyl-di-(1,2,4)-triazole and anappropriately substituted alcohol in a suitable solvent mixture such astetrahydrofuran and dichloromethane and the like at temperatures rangingfrom room temperature to the reflux temperature of the solvent.

Referring to Methods 26 and 30, the carbamoyl amine derivatives utilizedas starting materials in Methods 3A-3C which are ultimately convertedinto amines 2, wherein at least one substituent of R₁-R₅ is defined asdialkylamino and X is defined above may be prepared by reaction ofappropriately substituted aldehydes in the presence of either sodiumcyanoboro-hydride or hydrogen gas and 10% palladium on carbon in asuitable solvent such as water, methanol, tetrahydrofuran mixtures ortoluene or the like at room temperature.

Referring to Methods 27 and 28, amines 2 wherein at least onesubstituent of R₁-R₅ is defined as hydroxy and X is defined above can beprepared by reaction of the corresponding ester such as acetate with anappropriate base such as sodium bicarbonate or sodium hydroxide in asuitable solvent mixture such as methanol-water mixtures at temperaturesranging from room temperature to the reflux temperature of the solvent.

Referring to Method 29, amines 2 wherein at least one substituent ofR₁-R₅ is defined as 2-hydroxybenzamido and X is defined above can beprepared by reaction of the corresponding N-(4-aminophenyl)phthalimidewith lithium borohydride in an appropriate solvent such astetrahydrofuran, diethyl ether, or the like at room temperature.

The intermediate amines 2 wherein R₁-R₅ are defined as above and Xequals either —CH₂— or —(CH₂)₂— can be prepared by the followingprocedures:

a) reduction of an appropriately substituted benzo- orphenylacetonitrile with borane-dimethylsulfide complex in a suitablesolvent such as ethylene glycol dimethyl ether, tetrahydrofuran or thelike a temperatures ranging from room temperature to the refluxtemperature of the solvent. (Method 44);

b) reduction under one or more atmospheres of hydrogen in the presenceof a suitable catalyst such as 5% or 10% palladium on carbon and an acidsuch as 4-methyl-benzenesulfonic acid, hydrochloric acid or the like ina suitable solvent such as ethylene glycol monomethyl ether, ethylacetate, ethanol or the like at room temperature. (Method 50);

c) reduction with lithium aluminum hydride in a suitable solvent such astetrahydrofuran or diethyl ether at temperatures ranging from 0° C. toroom temperature. (Method 51);

The unsaturated nitro precursors which are utilized as startingmaterials in Method 51 and are ultimately converted to amines 2 whereinR₁-R₅ are defined as above and X equals —(CH₂)₂— can be prepared byreaction of an appropriately substituted benzaldehyde with nitro-methanein the presence of ammonium acetate in a suitable solvent such as aceticacid at temperatures ranging from room temperature to the refluxtemperature of the solvent.(Method 53); The benzaldehydes, utilized asstarting materials in Method 53, can be prepared by diisobutylaluminumhydride reduction of an appropriately substituted benzonitrile. (Method52) The substituted benzonitriles, utilized as starting materials inMethod 52, can be prepared from the corresponding aryl bromide byreaction with copper cyanide in a suitable solvent such asN,N-dimethylformamide at temperatures ranging from room temperature tothe reflux temperature of the solvent. (Method 59)

For amines 2, wherein R₁-R₅ is defined as above and X equals either—O(CH₂)₂NH₂ or —S(CH)₂NH₂, the requisite nitrile precursors may beprepared by reaction of an appropriately substituted phenol orthiophenol with bromoacetonitrile in the presence of a suitable basesuch as potassium carbonate in an appropriate solvent such as acetone atroom temperature according to Method 49.

Alternatively, for amines 2, wherein R₁-R₅ are defined as above and Xequals —(CH₂)₃—, the nitrile precursors can be prepared essentiallyaccording to the procedure of Wilk, B. Synthetic Comm. 23, 2481 (1993),by reaction of an appropriately substituted phenethanol with acetonecyanohydrin and triphenylphosphine in the presence of a suitableazodicarboxylate such as diethyl azodicarboxylate in an appropriatesolvent such as diethyl ether or tetrahydrofuran or the like attemperatures ranging from 0° C. to room temperature. (Method 54)

Alternatively, intermediate amines 2 wherein R₁-R₅ are defined as aboveand X equals —(CH(CH₃))— can be prepared by acid or base catalyzedhydrolysis of the corresponding formamide using an appropriate acidcatalyst such as 6N hydrochloric acid or a suitable base catalyst suchas 5N sodium or potassium hydroxide in an appropriate solvent mixturesuch as water and methanol or water and ethanol at temperatures rangingfrom room temperature to the reflux temperature of the solvent. (Method46)

The formamide precursors utilized as starting materials in Method 46 andwhich are ultimately converted into amines 2, are prepared according toMethod 45 by treatment of an appropriately substituted acetophenone withammonium formate, formic acid and formamide at temperatures ranging fromroom temperature to the reflux temperature of the solvent.

Alternatively, amines 2 wherein R₁-R₅ are defined as above and X equals—(CH(CH₃))— can be prepared by reduction of an appropriately substitutedO-methyl oxime in the presence of sodium borohydride and zirconiumtetrachloride in a suitable solvent such as tetrahydrofuran or diethylether at room temperature Method 48 essentially according to theprocedure of Itsuno, S., Sakurai, Y., Ito, K. Synthesis 1988, 995. Therequisite O-methyl oximes can be prepared from the correspondingacetophenone by reaction with methoxylamine hydrochloride and pyridinein a suitable solvent such as ethanol or methanol at temperaturesranging from room temperature to the reflux temperature of the solvent.(Method 47)

Amines 2 for which R₁-R₅ are defined as above and X equals —CH(J)— whereJ is defined as above, can be prepared by reduction of the appropriatelysubstituted ketone by the methods described above (Methods 45, 47, and48). These requisite ketones, when not commercially available, can beprepared by reaction of a suitably substituted benzaldehyde with anappropriate organometallic reagent such as phenyllithium,isopropylmagnesium bromide or ethylmagnesium bromide or the like in asuitable solvent such as diethyl ether or tetrahydrofuran attemperatures ranging from −78° C. to 0° C. (Method 57) The resultingalcohols can be oxidized to the corresponding ketone with an appropriateoxidizing agent such as chromium trioxide in aqueous sulfuric acid andacetone or pyridinium chlorochromate or pyridium dichromate in anappropriate solvent such as dichloromethane or the like at roomtemperature. (Method 58)

The intermediate anilines 5 may be prepared as previously describedMethod 3A. Thus treating phenyl carbamic acid tert-butyl ester 6, G isdescribed as above, with neat trifluoroacetic acid at room temperaturefollowed by neutralization with aqueous sodium hydroxide affords thedesired anilines 5. The requisite carbamic acid esters 6, wherein G isdescribed as above, are prepared as shown in Method 2C by reaction ofsubstituted acid chlorides, 8, where G is described as above, and4-aminophenylcarbamic acid tert-butyl esters 7 in the presence oftriethylamine in an appropriate solvent such as dichloromethane,dimethylsulfoxide, or dimethylformamide or mixtures thereof. Carboxylicacid chlorides 8 are either commercially available or prepared from thecorresponding carboxylic acid by reaction with oxalyl chloride in asuitable solvent such as dichloromethane at room temperature.

Alternatively, carbamic acid esters 6, wherein G is described as above,are prepared as shown in Method 2E by reaction of substituted carboxylicacids 8a, wherein G is described as above, and an appropriatelysubstituted 4-aminophenyl carbamic acid tert-butyl esters 7 in thepresence of a suitable coupling agent such asbenzotriazole-1-yloxy-tris-(dimethylamino)phosphoniumhexafluorophosphate,2-(1H-benzotriazole-1-yloxy)-1,1,3,3-tetramethyluroniumhexafluorophosphage, dicyclohexyl carbodiimide or the like and in thepresence of a tertiary amine base such as triethylamine ordiisopropylethylamine in a suitable solvent such as dichloromethane,dimethylformamide and the like, at room temperature to produce thecorresponding arylaminoamide.

Carboxylic acids 8a are either commercially available or are preparedaccording to literature methods. For example, when G is a substitutedthiadiazole, the acid is available from the corresponding carboxylicacid ester by reaction with an appropriate base such as sodium orpotassium hydroxide in a suitable solvent mixture such as methanol orethanol and water at room temperature.

Similarly, when G is either substituted or unsubstituted thiazole,substituted or unsubstituted oxazole, substituted or unsubstitutedisothiazole, or substituted or unsubstituted isoxazole, when notcommercially available, the corresponding carboxylic acid 8a isavailable from the corresponding ethyl or methyl ester by reaction withan appropriate base such as sodium or pottasium hydroxide in a suitablesolvent mixture such as methanol or ethanol and water at roomtemperature. These esters are either commercially available or can beprepared according to literature methods.

When the carboxylic acid ester precursors which are ultimately convertedto acids 8 are not commercially available, they may be prepared bymethods known in the literature. For example,5-substituted-1,2,3-thiadiazole-4 carboxylic acid esters may be preparedessentially according to the procedure of Caron, M J. Org. Chem. 51,4075 (1986) and Taber, D. F., Ruckle, R. E. J. Amer. Chem. Soc. 108,7686 (1986). Thus, according to Method 21, treatment of a beta-ketocarboxylic acid ester with 4-methylbenzenesulfonyl azide ormethanesulfonyl azide or the like in the presence of a tertiary aminebase such triethylamine or diisopropylethylamine in a suitable solventsuch as acetonitrile affords the corresponding diazo-beta-ketocarboxylic acid ester. Treatment of this compound with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide in asuitable solvent such as benzene or toluene or the like at temperaturesranging from room temperature to the reflux temperature of the solventgives the desired 5-substituted-1,2,3-thiadiazole-4-carboxylic acidester.

Alternatively, 4-substituted-1,2,3-thiadiazole-5-carboxylic acid estersmay be prepared essentially according to the procedure of Shafiee, A.,Lalezari, I., Yazdani, S., Shahbazian, F. M., Partovi, T. J.Pharmaceutical Sci. 65, 304 (1976). Thus, according to Method 22 and 23,reaction of an appropriately substituted beta-keto carboxylic acid esterin a suitable alcoholic solvent such as methanol or ethanol with anaqueous solution semicarbazide hydrochloride at temperatures rangingfrom room temperature to the reflux temperature of the solvent in thepresence of a suitable base such as pyridine gives correspondingsemicarbazone derivative. Treatment of this compound with neat thionylchloride at 0° C. followed by treatment with an excess aqueous solutionof sodium bicarbonate affords the corresponding4-substituted-1,2,3-thiadiazole -5-carboxylic acid esters.

4-carboalkoxythiazoles are prepared essentially according to theprocedure of Schöllkopf, U., Porsch, P., Lau, H. Liebigs Ann. Chem 1444(1979). Thus, according to Method 55 and 56, reaction of ethylisocyanoacetate with N,N-dimethylformamide dimethyl acetal in a suitablealcoholic solvent such as ethanol at room temperature gives thecorresponding 3-dimethylamino-2-isocyano-acrylic acid ethyl ester. Asolution of this compound in a suitable solvent such as tetrahydrofuranis treated with gaseous hydrogen sulfide in the presence of a suitabletertiary amine base such as triethylamine or diiso-propylethylamine orthe like at room temperature to give the corresponding4-carboethoxy-thiazole.

Additional appropriately substituted thiazoles may be preparedessentially according to the procedure of Bredenkamp, M. W., Holzafel,C. W., van Zyl, W. J. Synthetic Comm. 20, 2235 (1990). Appropriateunsaturated oxazoles are prepared essentially according to the procedureof Henneke, K. H., Schöllkopf, U., Neudecker, T. Liebigs Ann. Chem. 1979(1979). Substituted oxazoles may be prepared essentially according tothe procedures of Galeotti, N., Montagne, C., Poncet, J., Jouin, P.Tetrahedron Lett. 33, 2807, (1992) and Shin, C., Okumura, K., Ito, A.,Nakamura, Y. Chemistry Lett. 1305, (1994).

The following specific examples are illustrative, but are not meant tobe limiting of the present invention.

EXAMPLE 1 METHOD 1A 4-Methoxy-3-trifluoromethyl-phenylamine

A suspension of 4-methoxy-3-trifluoromethyl-nitrobenzene (2.2 g) andiron powder (1.68 g) in ethanol (35 mL) and water (15 mL) is treatedwith a solution of concentrated hydrochloric acid (0.42 mL) in ethanol(6 mL) and water (3 mL) and the mixture is heated to reflux forapproximately 1 hour. The mixture is then cooled, filtered, andconcentrated under reduced pressure. The resulting oil is dissolved inethyl acetate and extracted three times with 5% aqueous hydrochloricacid. The pooled acidic extracts are then cooled in an ice bath andbasified with solid potassium carbonate, then extracted with ethylacetate. These organic extracts are washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, concentrated underreduced pressure, then passed through a short column of silica gel(ethyl acetate is used as the eluant) to provide the desired compound asan amber oil.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

25 p 2,6-Dichloro-benzene-1,4-diamine

3-Chloro-4-methylsulfanyl-phenylamine

2,6-Dibromo-benzene-1,4-diamine

3-Chloro-4-trifluoromethyl-phenylamine

3-Chloro-4-ethylsulfanyl-phenylamine

4-Methoxy-3-trifluoromethyl-phenylamine

3,5-Dichloro-4-methoxy-2-methyl-phenylamine

5-Chloro-2-ethoxy-4-methoxy-phenylamine

5-Chloro-4-ethoxy-2-methoxy-phenylamine

5 5-Iodo-2,4-dimethoxy-phenylamine

3,5-Diiodo-2,4-dimethoxy-phenylamine

3,5-Dibromo-2,4-dimethoxy-phenylamine

5-Chloro-2-methoxy-4-methyl-phenylamine

2-Chloro-N(1),N(1)-dimethyl-benzene-1,4-diamine

3-Chloro-4-piperidin-1-yl-phenylamine

3-Chloro-4-pyrrolidin-1-yl-phenylamine

N(1)-Benzyl-2-chloro-benzene-1,4-diamine

3-Chloro-4-(4-methyl-piperazin-1-yl)-phenylamine

2-Chloro-N(1)-methyl-N(1)-(1-methyl-piperidin-4-yl)-benzene-1,4-diamine

2-Chloro-N(1)-methyl-N(1)-(1-methyl-pyrrolidin-3-yl)-benzene-1,4-diamine

2-Chloro-N(1)-methyl-N(1)-phenyl-benzene-1,4-diamine

N(1)-(1-Benzyl-pyrrolidin-3-yl)-2-chloro-N(1)-methyl-benzene-1,4-diamine

2-Chloro-N(1)-cyclopentyl-N(1)-methyl-benzene-1,4-diamine

2-[(4-Amino-2-chloro-phenyl)-(2-hydroxy-ethyl)-amino]-ethanol

2-Chloro-N(1)-hexyl-N(1)-methyl-benzene-1,4-diamine

2-Chloro-N(1)-isobutyl-N(1)-methyl-benzene-1,4-diamine

2-[(4-Amino-2-chloro-phenyl)-methyl-amino]-ethanol

2-Chloro-N(1)-(3-dimethylamino-propyl)-N(1)-methyl-benzene-1,4-diamine

2-Chloro-N(1)-(2-dimethylamino-ethyl)-N(1)-methyl-benzene-1,4-diamine

2-Chloro-N(1)-(2-dimethylamino-ethyl)-benzene-1,4-diamine

N(1)-(1-Benzyl-piperidin-4-yl)-2-chloro-benzene-1,4-diamine

2-Chloro-N(1)-(2-methoxy-ethyl)-N(1)-methyl-benzene-1,4-diamine

2-Chloro-N(1)-(3-dimethylamino-propyl)-benzene-1,4-diamine

N(1)-(1-Benzyl-pyrrolidin-3-yl)-2-chloro-benzene-1,4-diamine

3-Chloro-4-(1-methyl-piperidin-4-yloxy)-phenylamine

3-Chloro-4-(2-dimethylamino-ethoxy)-phenylamine

3-Chloro-4-(3-dimethylamino-propoxy)-phenylamine

3-Chloro-4-(1-methyl-pyrrolidin-3-yloxy)-phenylamine

3-Chloro-4-cyclohexyloxy-phenylamine

EXAMPLE 2 METHOD 1B 4-Bromo-2,4-dimethoxy-phenylamine

A suspension of 4-bromo-2,4-dimethoxy-nitrobenzene (0.48 g) and ironpowder (0.42 g) in acetic acid (10 mL) and ethanol (10 mL) is heated to120° C. for approximately 5 hours. The mixture is then cooled, filtered,and concentrated under reduced pressure. Water is added and the mixtureis cooled in an ice bath and neutralized with solid potassium carbonateand then extracted with dichloromethane. These organic extracts arewashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, concentrated under reduced pressure, thenchromatographed over silica gel (20% ethyl acetate in hexanes is used asthe eluant) to provide the desired compound as an amber oil.

EXAMPLE 3 METHOD 1C (4-Amino-2,6-dichloro-phenoxy)-acetic acidtert-butyl ester

A soution of (4-nitro-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester(1 g) in ethanol (17 mL) and water (8.6 mL) is treated with iron powder(0.861 g) and ammonium chloride (86 mg) and the mixture is heated toreflux for approximately 1 hour. The mixture is then filtered andconcentrated under reduced pressure. The resulting oil is partitionedbetween water and ethyl acetate, and the organic phase is then washedwith saturated aqueous sodium chloride, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to provide the desiredcompound as a pale yellow solid. P Using the above procedure andappropriate starting materials the following compounds were prepared:

4-Chloro-benzene-1,2-diamine

N-(4-Amino-2-chloro-phenyl)-acetamide

(4-Amino-2,6-dichloro-phenoxy)-acetonitrile

(4-Amino-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester

(2-Amino-4-chloro-5-methoxy-phenoxy)-acetonitrile

(4-Amino-2-chloro-5-methoxy-phenoxy)-acetic acid methyl ester

(4-Amino-2-chloro-5-methoxy-phenoxy)-acetic acid tert-butyl ester

(2-Amino-4-chloro-5-methoxy-phenoxy)-acetic acid tert-butyl ester

N(1)-Benzyl-4-chloro-5-methoxy-benzene-1,2-diamine

N-(4-Amino-2-chloro-phenyl)-2-fluoro-benzamide

N-(4-Amino-5-chloro-2-hydroxy-phenyl)-acetamide

N-(4-Amino-5-chloro-2-hydroxy-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-2-chloro-phenyl)-amide

(4-Amino-2-chloro-phenyl)-carbamic acid ethyl ester

N-(4-Amino-5-chloro-2-methyl-phenyl)-acetamide

N-(4-Amino-5-chloro-2-methyl-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-5-chloro-2-methyl-phenyl)amide

N-(4-Amino-3-chloro-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-3-chloro-phenyl)-amide

N-(4-Amino-2-chloro-phenyl)-2-dimethylamino-acetamide

N-(4-Amino-2-chloro-phenyl)-2-piperidin-1-yl-acetamide

N-(4-Amino-2-chloro-phenyl)-2-morpholin-4-yl-acetamide

N-(4-Amino-2-chloro-phenyl)-methanesulfonamide

N-(4-Amino-2-chloro-phenyl)-benzamide

N-(4-Amino-2-chloro-phenyl)-2-diethylamino-acetamide

N-(4-Amino-2-chloro-phenyl)-2-pyrrolidin-1-yl-acetamide

N-(4-Amino-2-chloro-phenyl)-2-azepan-1-yl-acetamide

N-(4-Amino-2-chloro-phenyl)-2-(2-methyl-piperidin-1-yl)-acetamide

N-(4-Amino-2-chloro-phenyl)-2-(3-methyl-piperidin-1-yl)-acetamide

3-Chloro-benzene-1,2-diamine

4-Chloro-N,N-dimethyl-benzene-1,2-diamine

EXAMPLE 4 METHOD 1D 3,5-Dichloro-4-phenoxy-phenylamine

To a slurry of 3,5-dichloro-4-phenoxy-nitrobenzene (6.1 g) and tinpowder (12 g) is added dropwise concentrated hydrochloric acid (60 mL).Ethanol (60 mL) is added and the mixture is heated to reflux forapproximately 1 hour. The mixture is then cooled in an ice bath andbasified by addition of solid sodium hydroxide. The resulting suspensionis filtered through a pad of diatomaceous earth and extracted threetimes with ethyl acetate. The combined organic extracts are then washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure to provide the desiredproduct as a yellow solid. Recrystallization from ethyl acetate-hexanesprovided the product as a pale yellow solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

1-Furan-2-yl-ethylamine

3-Chloro-4-isopropoxy-phenylamine

2-Butoxy-5-chloro-4-methoxy-phenylamine

3,5-Dichloro-2-methoxy-4-methyl-phenylamine

2-Benzyloxy-5-chloro-4-methoxy-phenylamine

4-Benzyloxy-5-chloro-2-methoxy-phenylamine

5-Fluoro-2,4-dimethoxy-phenylamine

(4-Amino-2,6-dichloro-phenoxy)-acetic acid ethyl ester

3,5-Dichloro-4-phenoxy-phenylamine

2-(4-Amino-2-chloro-5-methoxy-phenoxy)-acetamide

(4-Amino-2-chloro-5-methoxy-phenoxy)-acetonitrile

2-(2-Amino-4-chloro-5-methoxy-phenoxy)-ethanol

2-(4-Amino-2-chloro-5-methoxy-phenoxy)-ethanol

4-(4-Amino-2-chloro-5-methoxy-phenoxy)-butyronitrile

4-Amino-2-chloro-5-methoxy-phenol

2-Amino-4-chloro-5-methoxy-phenol

5-Chloro-4-methoxy-2-morpholin-4-yl-phenylamine

4-Chloro-5-methoxy-N(1),N(1)-dimethyl-benzene-1,2-diamine

5-Chloro-4-methoxy-2-piperidin-1-yl-phenylamine

5-Chloro-4-methoxy-2-pyrrolidin-1-yl-phenylamine

2-Chloro-N(1)-cyclohexyl-N(1)-methyl-benzene-1,4-diamine

N(2)-Benzyl-4-methoxy-benzene-1,2-diamine

2-(4-Amino-2-chloro-phenoxy)-ethanol

2-Chloro-N(1)-cyclohexyl-N(1)-ethyl-benzene-1,4-diamine

4-Butoxy-3-chloro-phenylamine

(4-Amino-2-chloro-phenoxy)-acetonitrile

2-Chloro-N(1)-cyclohexyl-benzene-1,4-diamine

2-Chloro-N(1),N(1)-dipropyl-benzene-1,4-diamine

3-Chloro-4-(2,2,2-trifluoro-ethoxy)-phenylamine

3-Chloro-4-(octahydro-quinolin-1-yl)-phenylamine

N(1)-Allyl-2-chloro-N(1)-cyclohexyl-benzene-1,4-diamine

N-(4-Amino-2-methoxy-5-methyl-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-2-methoxy-5-methyl-phenyl)amide

(4-Amino-naphthalen-1-yl)-2-fluoro-benzamide

3-Chloro-N,N-dimethyl-benzene-1,2-diamine

3-Chloro-4-propoxy-phenylamine

3-Iodo-4-methoxy-phenylamine

3-Chloro-2,4-dimethoxy-aniline

3-Bromo-4-methoxy-phenylamine

3-Chloro-4-ethoxy-phenylamine

EXAMPLE 5 Method 1E (4-Amino-phenyl)-carbamic acid isobutyl ester

To a solution of N-(4-Nitro-phenyl)-isobutyrlamide (2.0 g) in 100 mLethylene glycol monomethyl ether (100 mL) is added 10% palladium oncarbon (275 mg). The mixture is hydrogenated for 2 hours at roomtemperature under 30 psi of hydrogen on a Parr hydrogenation apparatus.The catalyst is then removed by filtration through diatomaceous earthand the filtrate is evaporated to dryness under reduced pressure byazeotroping three times with heptane. Trituration of the residue withheptane provides the desired product as a white solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

2-Methyl-3H-benzoimidazol-5-ylamine

N-(4-Amino-phenyl)-formamide

1H-Benzoimidazol-5-ylamine

(4-Amino-phenyl)-carbamic acid isobutyl ester

N-(4-Amino-phenyl)-isobutyramide

N-(5-Amino-pyridin-2-yl)-2-methyl-benzamide

Furan-2-carboxylic acid (5-amino-pyridin-2-yl)-amide

N-(5-Amino-pyridin-2-yl)-2-fluoro-benzamide

[6-(2,2,2-Trifluoro-acetylamino)-pyridin-3-yl]-carbamic acid tert-butylester

N-(5-Amino-pyridin-2-yl)-2,2,2-trifluoro-acetamide

(4-Amino-benzyl)-carbamic acid tert-butyl ester

2-(3,5-Bis-trifluoromethyl-phenyl)-ethylamine

1-tert-Butyl-1H-imidazol-2-ylamine

3-(3-Dimethylamino-propyl)-5-trifluoromethyl-phenylamine

EXAMPLE 6 METHOD 1F N-(4-Amino-2-methylphenyl)-2-fluorobenzamide

A mixture of 2-fluoro-N-(2-methyl-4-nitrophenyl)benzamide (4.55 g),cyclohexene (30 mL), ethanol (70 mL), water (30 mL) and 10% palladium oncharcoal (3 g) is heated at reflux for 30 minutes. The mixture isfiltered through diatomaceous earth and concentrated under reducedpressure. The resulting oil is dissolved in 50 mL of ethyl acetate andcooled at 4° C. for 12 hours. Filtration provides the product as a tansolid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N-(4-Amino-2-methyl-phenyl)-acetamide

2-Methyl-benzooxazol-6-ylamine

N-(4-Amino-3-methoxy-phenyl)-acetamide

2-Acetylamino-5-amino-benzoic acid

N-(4-Amino-phenyl)-acetamide

[4-(3-Amino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Amino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

N-(4-Amino-2-cyano-phenyl)-acetamide

N-(4-Amino-2,5-dimethoxy-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-2,5-dimethoxy-phenyl)-amide

N-(4-Amino-2-cyano-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-2-methoxy-phenyl)-amide

N-(4-Amino-2-methoxy-phenyl)-2-fluoro-benzamide

N-(4-Amino-2-methoxy-5-methyl-phenyl)-acetamide

N-(4-Amino-2-benzoyl-phenyl)-acetamide

N-(4-Amino-2-benzoyl-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-2-benzoyl-phenyl)-amide

N-(4-Amino-3-methyl-phenyl)-acetamide

N-(4-Amino-3-methyl-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-3-methyl-phenyl)-amide

5-Amino-2-[(2-fluorobenzoyl)amino]-N-phenylbenzamide

Furan-2-carboxylic acid (4-amino-2-phenylcarbamoyl-phenyl)amide

N-(4-Amino-naphthalen-1-yl)-acetamide

Furan-2-carboxylic acid (4-amino-naphthalen-1-yl)-amide

N-(4-Amino-2-trifluoromethyl-phenyl)-acetamide

Furan-2-carboxylic acid (4-amino-2-cyano-phenyl)-amide

Furan-2-carboxylic acid (4-amino-2-trifluoromethyl-phenyl)-amide

N-(4-Amino-2-methyl-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-2-methyl-phenyl)-amide

5-Amino-2-(2-fluoro-benzoylamino)-benzoic acid

5-Amino-2-[(furan-2-carbonyl)-amino]-benzoic acid

N-(4-Amino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide

N-(4-Amino-3-methyl-phenyl)-2,6-difluoro-benzamide

N-(4-Amino-3-trifluoromethyl-phenyl)-acetamide

N-(4-Amino-3-trifluoromethyl-phenyl)-2-fluoro-benzamide

N-(4-Amino-2-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide

N-(4-Amino-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide

N-(4-Amino-2-trifluoromethyl-phenyl)-2-fluoro-N-(2-fluoro-benzoyl)-benzamide

N-(4-Amino-2-trifluoromethyl-phenyl)-2-fluoro-benzamide

EXAMPLE 7 METHOD 1GN-(4Amino-2-chlorophenyl)-2-thiomorpholino-4-yl-acetamide

A solution of N-(2-chloro-4-nitrophenyl)-2-thiomorpholino-4-yl-acetamide(3.02 g) in ethanol (200 mL) is added to a solution of sodiumthiosulfate (12 g) in water (60 mL). The mixture is heated at reflux for12 hours, cooled and poured into water. The mixture is then extractedwith ethyl acetate. The ethyl acetate solution is washed twice withsaturated aqueous sodium chloride, dried over anhydrous potassiumcarbonate, filtered through a pad of diatomaceous earth and concentratedunder reduced pressure to give an oil. Toluene is added and the solutionchilled to give the desired product as a light orange crystalline solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N-(4-Amino-2-chloro-phenyl)-2-thiomorpholin-4-yl-acetamide

N-(4-Amino-2-chloro-phenyl)-2-dipropylamino-acetamide

EXAMPLE 8 METHOD 2A (3-Chloro-4-iodo-phenyl)-carbamic acid tert-butylester

To a solution of 3-chloro-4-iodo-aniline (10 g) in tetrahydrofuran (40mL) containing diiso-propylethylamine (6.9 mL) is addeddi-tert-butyl-dicarbonate (8.6 g) and the mixture is heated to reflux.After approximately 15 hours additional portions ofdiisopropylethylamine (6.9 mL) and di-tert-butyl-dicarbonate (21 g) isadded and heating is continued for approximately 24 hours. The solutionis then cooled, concentrated under reduced pressure, diluted with ethylacetate, and washed successively three times with 5% aqueoushydrochloric acid then once with saturated aqueous sodium chloride. Thesolution is dried over anhydrous sodium sulfate then concentrated underreduced pressure to provide the desired crude product as a brown oil.Crystallization is induced by addition of hexanes, and the collectedsolid material is recrystallized from hexanes to give the desiredproduct as a white solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N′-(4-Nitro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester

(3-Chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester

(4-Bromo-3-chloro-phenyl)-carbamic acid tert-butyl ester

(3-Chloro-4-vinyl-phenyl)-carbamic acid tert-butyl ester

(3-Chloro-4-methylsulfanyl-phenyl)-carbamic acid tert-butyl ester

(4-Amino-3-chloro-phenyl)-carbamic acid tert-butyl ester

(4-Chloro-2-nitro-phenyl)-carbamic acid tert-butyl ester

(3-tert-Butoxycarbonylamino-5-chloro-phenyl)-carbamic acid tert-butylester

(4-Nitro-benzyl)-carbamic acid tert-butyl ester

(3-Bromo-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester

(2-Amino-3-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butylester

EXAMPLE 9 METHOD 2B (3-Chloro-4-vinyl-phenyl)-carbamicacid2-trimethylsilanyl-ethyl ester

To a solution of 3-chloro-4-vinyl-phenylamine (3.4 g) inN,N-dimethylformamide (44 mL) containing diisopropylethylamine (5.8 mL)is added 1-[2-(trimethylsilyl)-ethoxycarbonyl-oxy]benzotriazole (7.1 g)and the mixture is stirred at room temperature under an atmosphere ofargon for three days. The solution is then diluted with water andextracted three times with diethyl ether. The combined organic extractsare washed successively with water, saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The resulting residue is chromatographed over silica gel (10%ethyl acetate in hexanes is used as the eluant) to provide the desiredproduct as a yellow oil.

EXAMPLE 10 METHOD 2C [4-(2-Fluoro-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

To a solution of mono-N-(t-butoxycarbonyl)-1,4-phenylenediamine (1.58 g)and triethylamine (1.50 mL) in 25 mL of dichloromethane is addedo-fluorobenzoyl chloride (1.20 g). A solid formed immediately forms andis filtered and washed with fresh solvent to yield a white solid, 1.90g.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N-(3-Methoxy-4-nitro-phenyl)-acetamide

N-(4-Amino-phenyl)-isobutyrlamide

2,2,2-Trifluoro-N-(2-methoxy-4-nitro-phenyl)-acetamide

[4-(2-Methyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

Acetic acid 2-(4-tert-butoxycarbonylamino-phenylcarbamoyl)-phenyl ester

[4-(4-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(3-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(3-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(4-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2,2-Dimethyl-propionylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Bromo-acetylamino)-pheny]-carbamic acid tert-butyl ester

[4-(2,2,2-Trifluoro-acetylamino)-phenyl]-carbamic acid tert-butyl ester

(4-Benzoylamino-phenyl)-carbamic acid tert-butyl ester

(4-Methanesulfonylamino-phenyl)-carbamic acid tert-butyl ester

(4-Phenylacetylamino-phenyl)-carbamic acid tert-butyl ester

{4-[(Thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

[4-(3-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(3-Acetylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(3-Methanesulfonylamino-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

Ethyl[3-[[[4-[[(1,1-dimethylethoxy)carbonyl]amino]phenyl]amino]carbonyl]phenyl]-carbamate

[4-(2-Trifluoromethyl-benzoylamino)-phenyl]-carbamic acid tert-butylester

[4-(2,6-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Bromo-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

{4-[(Benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

{4-[(Pyridine-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(Naphthalene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(Naphthalene-1-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(3-Bromo-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

{4-[(Biphenyl-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

N-(4-tert-Butoxycarbonylamino-phenyl)-phthalamic acid

[4-(2,3-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2,5-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2,4-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Acetylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2-Methanesulfonylamino-benzoylamino)-phenyl]-carbamic acidtert-butyl ester

[4-(2,3,4-Trifluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(2,3,4,5,6-Pentafluoro-benzoylamino)-phenyl]-carbamic acid tert-butylester

N-(4-tert-Butoxycarbonylamino-phenyl)-isophthalamic acid methyl ester

2-Methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide

[4-(3-Benzyloxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(3-Butoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

{4-[(5-Difluoromethyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

{4-[(Thiophene-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(5-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(5-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

(4-Hexanoylamino-phenyl)-carbamic acid tert-butyl ester

[4-(2-Thiophen-2-yl-acetylamino)-phenyl]-carbamic acid tert-butyl ester

{4-[(Pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(4-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(Furan-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

(4-Phenoxycarbonylamino-phenyl)-carbamic acid tert-butyl ester

{4-[(Benzo[1,3]dioxole-4-carbonyl)-amino]-phenyl)-carbamic acidtert-butyl ester

[4-(3-Trifluoromethoxy-benzoylamino)-phenyl]-carbamic acid tert-butylester

N-(2,5-Dimethoxy-4-nitro-phenyl)-2-fluoro-benzamide

{4-[(Furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

[4-(2-Phenoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester

{4-[(5-Nitro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(5-Chloro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(3-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

[4-(2-Methoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester

{4-[(4-Furan-3-yl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

{4-[(5-tert-Butyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

N-[3-Cyano-4-(2,2,2-trifluoro-acetylamino)-phenyl]-2-fluoro-benzamide

Furan-2-carboxylic acid[3-cyano-4-(2,2,2-trifluoro-acetylamino)-phenyl]amide

N-(4-Acetylamino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide

2,2,2-Trifluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-acetamide

N-(4-Acetylamino-2-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide

2-Fluoro-N-[4-(2,2,2-trifluoro-acetylamino)-3-trifluoromethyl-phenyl]benzamide

Furan-2-carboxylic acid[4-(2,2,2-trifluoro-acetylamino)-3-trifluoromethyl-phenyl]amide

2-Fluoro-N-(2-methyl-benzooxazol-6-yl)-benzamide

4-(2-Fluoro-benzoylamino)-2-hydroxy-benzoic acid phenyl ester

{4-[(Isoxazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

N-(4-Acetylamino-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide

2-Fluoro-N-[3-methoxy-4-(2,2,2-trifluoro-acetylamino)-phenyl]benzamide

2-Fluoro-N-(2-fluoro-benzoyl)-N-(4-nitro-2-trifluoromethyl-phenyl)benzamide

{4-[(1H-Pyrazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(1H-Imidazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(5-Methyl-[1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

{4-[(5-Furan-3-yl-[1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

2,2,2-Trifluoro-N-(S-nitro-pyridin-2-yl)-acetamide

{4-[(1-Methyl-1H-pyrazole-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

4-(2-Fluoro-benzoylamino)-2-hydroxy-benzoic acid methyl ester

N-(5-Chloro-2,4-dimethoxy-phenyl)-oxalamic acid

Isoxazole-5-carboxylic acid (4-amino-phenyl)-amide

2-Fluoro-N-(4-nitro-benzyl)-benzamide

Furan-2-carboxylic acid 4-nitro-benzylamide

N-[3-Chloro-5-(2,2,2-trifluoro-acetylamino)-phenyl]-2,2,2-trifluoro-acetamide

N-(3-Amino-5-chloro-phenyl)-2,2,2-trifluoro-acetamide

[4-(2-Fluoro-benzoylamino)-benzyl]-carbamic acid tert-butyl ester

[4-(2,6-Difluoro-benzoylamino)-benzyl]-carbamic acid tert-butyl ester

2,6-Difluoro-N-(4-nitro-benzyl)-benzamide

{4-[(Furan-2-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester

N-(3-Amino-5-chloro-phenyl)-acetamide

[4-(3-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(4-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

[4-(4-Dimethylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

(4-Benzenesulfonylamino-phenyl)-carbamic acid tert-butyl ester

[4-(3-Trifluoromethyl-benzoylamino)-phenyl]-carbamic acid tert-butylester

2,2,2-Trifluoro-N-(5-nitro-pyrimidin-2-yl)-acetamide

EXAMPLE 11 METHOD 2D 2-Chloro-N-(2-chloro-4-nitrophenyl)acetamide

A solution of 2-chloro-4-nitroaniline (19.0 g) and chloroacetyl chloride(30 mL) in tetrahydrofuran (150 mL) is heated at reflux for 1 hour. Thesolution is cooled and concentrated under reduced pressure, giving a wetyellow solid. Ether (250 mL) is added and the yellow solid is collected.

Using the above procedure and appropriate starting materias thefollowing compounds were prepared:

N-(4-Nitro-3-trifluoromethyl-phenyl)-acetamide

(2-Chloro-4-nitro-phenyl)-carbamic acid ethyl ester

2-Acetylamino-5-nitro-benzoic acid

Furan-2-carboxylic acid (5-chloro-2-hydroxy-4-nitro-phenyl)-amide

Furan-2-carboxylic acid (2-methyl-4-nitro-phenyl)-amide

Furan-2-carboxylic acid (2-methoxy-4-nitro-phenyl)-amide

N-(2-Chloro-4-nitro-phenyl)-benzamide

2-Methoxy-N-(4-nitro-phenyl)-acetamide

N-(4-Nitro-phenyl)-acrylamide

N-(4-Nitro-phenyl)-isobutyrlamide

[4-)acryloylamino)-phenyl]carbamic acid tert-butyl ester

(4-Nitro-phenyl)-carbamic acid isobutyl ester

[1,2,3]Thiadiazole-4-carboxylic acid (5-nitro-pyridin-2-yl)-amide

Furan-2-carboxylic acid (5-nitro-pyridin-2-yl)-amide

2-Fluoro-N-(5-nitro-pyridin-2-yl)-benzamide

N-(2-Chloro-4-nitro-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (2,5-dimethoxy-4nitro-phenyl)-amide

N-(2-Cyano-4-nitro-phenyl)-2-fluoro-benzamide

2-Fluoro-N-(2-methoxy-4-nitro-phenyl)-benzamide

2-Methyl-N-(5-nitro-pyridin-2-yl)-benzamide

Furan-2-carboxylic acid (2-methoxy-5-methyl-4-nitro-phenyl)-amide

2-Fluoro-N-(2-methoxy-5-methyl-4-nitro-phenyl)-benzamide

N-(2-Benzoyl-4-nitro-phenyl)-acetamide

N-(2-Benzoyl-4-nitro-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (2-benzoyl-4-nitro-phenyl)-amide

N-(3-Methyl-4-nitro-phenyl)-acetamide

2-Fluoro-N-(3-methyl-4-nitro-phenyl)-benzamide

Furan-2-carboxylic acid (3-methyl-4-nitro-phenyl)-amide

2-Acetylamino-5-nitro-N-phenyl-benzamide

2-[(2-Fluorobenzoyl)amino]-5-nitro-N-phenylbenzamide

Furan-2-carboxylic acid (4-nitro-2-phenylcarbamoyl-phenyl)-amide

2-Fluoro-N-(4-nitro-naphthalen-1-yl)-benzamide

Furan-2-carboxylic acid (4-nitro-naphthalen-1-yl)-amide

N-(5-Chloro-2-hydroxy-4-nitro-phenyl)-acetamide

N-(5-Chloro-2-hydroxy-4-nitro-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (2-chloro-4-nitro-phenyl)-amide

N-(4-Nitro-2-trifluoromethyl-phenyl)-acetamide

Furan-2-carboxylic acid (2-cyano-4-nitro-phenyl)-amide

2-Fluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-benzamide

Furan-2-carboxylic acid (4-nitro-2-trifluoromethyl-phenyl)-amide

2-Fluoro-N-(2-methyl-4-nitro-phenyl)-benzamide

N-(5-Chloro-2-methyl-4-nitro-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (5-chloro-2-methyl-4-nitro-phenyl)-amide

2-(2-Fluoro-benzoylamino)-5-nitro-benzoic acid

2-[(Furan-2-carbonyl)-amino]-5-nitro-benzoic acid

N-(3-Chloro-4-nitro-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (3-chloro-4-nitro-phenyl)-amide

2,6-Difluoro-N-(3-methyl-4-nitro-phenyl)-benzamide

2-Fluoro-N-(4-nitro-3-trifluoromethyl-phenyl)-benzamide

Furan-2-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide

2-Chloro-N-(2-chloro-4-nitro-phenyl)-acetamide

N-(2-Chloro-4-nitrophenyl)methanesulfonamide

Furan-2-carboxylic acid[3-methoxy-4-(2,2,2-trifluoro-acetylamino)-phenyl]-amide

N-(2-Chloro-4-nitro-phenyl)-2,2,2-trifluoro-acetamide

EXAMPLE 12{4-[(4-Phenyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl

A solution of 1-(N-tert-butoxycarbonyl)-1,4-phenylenediamine (0.8 g) and4-phenyl-[1,2,3]thiadiazole-5-carboxylic acid (0.7 g) in dichloromethane(10 mL) is treated with triethylamine (1.3 mL) andbenzotriazole-1-yloxy-tris(dimethylamino)-phosphoniumhexa-fluorophosphate (1.6 g). After stirring at room temperature, thereaction is diluted with water and extracted with dichloromethane. Theorganic layer is washed with 0.5 N hydrochloric acid, saturated sodiumbicarbonate, and water then dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to give the desired product.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

{4-[(1H-Pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(Pyrazine-2-carbonyl)-amino]-phenyl)-carbamic acid tert-butyl ester

{4-[(5-Methyl-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

{4-[(1-Methyl-1H-pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

{4-[(Quinoline-8-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(Benzofuran-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(Isoquinoline-1-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[(Quinoline-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(Pyridine-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(Isoquinoline-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butylester

{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

{4-[(1H-[1,2,3]Triazole-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester

[4-(2-Methylsulfanyl-benzoylamino)-phenyl]-carbamic acid tert-butylester

{4-[(Quinoline-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

{4-[(4-Methyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

{4-[(4-Phenyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester

{4-[(1H-Indole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

[1,2,3]Thiadiazole-4-carboxylic acid 4-nitro-benzylamide

{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-benzyl}-carbamic acidtert-butyl ester

Acetic acid 4-(4-tert-butoxycarbonylamino-phenylcarbamoyl)-phenyl ester

{4-[(Quinoline-6-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester

EXAMPLE 13 METHOD 2F Acetic acid2-(4-tert-butoxycarbonylamino-2,6-dichloro-phenoxy)-ethyl ester

A solution of [3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acidtert-butyl ester (0.85 g) in pyridine (14 mL) is treated with aceticanhydride (1.24 mL) and the mixture is stirred at room temperature for15 hours. The solvent is removed under reduced pressure and the residuedissolved in ethyl acetate. This solution is then washed twice with 5%aqueous hydrochloric acid, once with saturated aqueous sodiumbicarbonate, and then with saturated aqueous sodium chloride. Thesolution is dried over anhydrous magnesium sulfate and the solvent isremoved under reduced pressure to provide the desired product as acolorless oil.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

Phenylsulfanyl-acetonitrile

Acetic acid 2-(4-tert-butoxycarbonylamino-2,6-dichloro-phenoxy)-ethylester

EXAMPLE 14 METHOD 2G (3,5-Dichloro-4-hydroxy-phenyl)-carbamic acidtert-butyl ester

To a solution of 2,6-dichloro-4-amino phenol (9.5 g) in tetrahydrofuran(130 mL) is added di-tert-butyl-dicarbonate (11.7 g) and the mixture isheated to reflux for approximately 15 hours. The solution is thencooled, concentrated under reduced pressure, diluted with ethyl acetate,and washed successively three times with 5% aqueous hydrochloric acidthen once with saturated aqueous sodium chloride. The solution is driedover anhydrous sodium sulfate then concentrated under reduced pressureto provide the desired crude product. This material is then trituratedwith cold dichloromethane to provide the product as a white solid.

Using the above procedure and appropriate starting materials thefollowing compound was prepared:

(3-Amino-5-chloro-phenyl)-carbamic acid tert-butyl ester

EXAMPLE 15 METHOD 3A 3,5-Dichloro-4-ethoxy-phenylamine

Trifluoroacetic acid (5 mL) is added to solid(3,5-dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester (0.97 g)and the mixture is stirred for approximately 45 minutes at roomtemperature. Water is then added, and the mixture is cooled in an icebath and basified with solid potassium carbonate. The solution isextracted three times with ethyl acetate and the combined organic phasesare washed with saturated aqueous sodium chloride then dried overanhydrous sodium sulfate. Concentration under reduced pressure andrecrystallization from hexanes provides the desired product as a paleyellow crystalline solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

5-Bromo-pyridin-3-ylamine

3-Chloro-4-methanesulfonyl-phenylamine

N-(4-Amino-phenyl)-2-methyl-benzamide

Acetic acid 2-(4-amino-phenylcarbamoyl)-phenyl ester

N-(4-Amino-phenyl)-4-fluoro-benzamide

N-(4-Amino-phenyl)-3-fluoro-benzamide

N-(4-Amino-phenyl)-2-fluoro-benzamide

N-(4-Amino-phenyl)-2-methoxy-benzamide

N-(4-Amino-phenyl)-3-methoxy-benzamide

N-(4-Amino-phenyl)-4-methoxy-benzamide

N-(4-Amino-phenyl)-2-phenyl-acetamide

N-(4-Amino-phenyl)-2,2-dimethyl-propionamide

N-(4-Amino-phenyl)-2,2,2-trifluoro-acetamide

Thiophene-2-carboxylic acid (4-amino-phenyl)-amide

1H-Pyrrole-2-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-3-nitro-benzamide

3-Acetylamino-N-(4-amino-phenyl)-benzamide

N-(4-Amino-phenyl)-3-dimethylamino-benzamide

N-(4-Amino-phenyl)-3-methanesulfonylamino-benzamide

N-(4-Amino-phenyl)-2-trifluoromethyl-benzamide

N-(4-Amino-phenyl)-2,6-difluoro-benzamide

N-(4-Amino-phenyl)-2-chloro-benzamide

N-(4-Amino-phenyl)-2-bromo-benzamide

N-(4-Amino-phenyl)-2-nitro-benzamide

Pyrazine-2-carboxylic acid (4-amino-phenyl)-amide

5-Methyl-thiophene-2-carboxylic acid (4-amino-phenyl)-amide

Quinoline-8-carboxylic acid (4-amino-phenyl)-amide

1-Methyl-1H-pyrrole-2-carboxylic acid (4-amino-phenyl)-amide

Benzo[b]thiophene-2-carboxylic acid (4-amino-phenyl)-amide

Benzofuran-2-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-isonicotinamide

Naphthalene-2-carboxylic acid (4-amino-phenyl)-amide

Naphthalene-1-carboxylic acid (4-amino-phenyl)-amide

Isoquinoline-1-carboxylic acid (4-amino-phenyl)-amide

Quinoline-2-carboxylic acid (4-amino-phenyl)-amide

3,5-Dichloro-4-ethoxy-phenylamine

4-Butoxy-3,5-dichloro-phenylamine

Isoquinoline-4-carboxylic acid (4-amino-phenyl)-amide

[1,2,3]Thiadiazole-4-carboxylic acid (4-amino-phenyl)-amide

1H-[1,2,3]Triazole-4-carboxylic acid (4-amino-phenyl)-amide

3-Bromo-thiophene-2-carboxylic acid (4-amino-phenyl)-amide

4-Benzyloxy-3,5-dichloro-phenylamine

2-(4-Amino-2,6-dichloro-phenoxy)-acetamide

(4-Amino-2,6-dichloro-phenoxy)-acetic acid methyl ester

[3-(4-Amino-phenylcarbamoyl)-phenyl]-carbamic acid ethyl ester

2-Amino-N-(4-amino-phenyl)-benzamide

Biphenyl-2-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-2,3-difluoro-benzamide

N-(4-Amino-phenyl)-2,5-difluoro-benzamide

N-(4-Amino-phenyl)-2,4-difluoro-benzamide

2-Acetylamino-N-(4-amino-phenyl)-benzamide

N-(4-Amino-phenyl)-2-methanesulfonylamino-benzamide

N-(4-Amino-phenyl)-2,3,4-trifluoro-benzamide

N-(4-Amino-phenyl)-2,3,4,5,6-pentafluoro-benzamide

N-(4-Amino-phenyl)-2-methylsulfanyl-benzamide

Acetic acid 2-(4-amino-2,6-dichloro-phenoxy)-ethyl ester

N-(4-Amino-phenyl)-isophthalamic acid methyl ester

N-(4-Amino-phenyl)-3-benzyloxy-benzamide

N-(4-Amino-phenyl)-3-butoxy-benzamide

[3-(4-Amino-phenylcarbamoyl)-phenoxy]-acetic acid ethyl ester

Pyridine-2-carboxylic acid (4-amino-phenyl)-amide

Quinoline-4-carboxylic acid (4-amino-phenyl)-amide

5-Methyl-furan-2-carboxylic acid (4-amino-phenyl)-amide

5-Difluoromethyl-furan-2-carboxylic acid (4-amino-phenyl)-amide

1H-Indole-2-carboxylic acid (4-amino-phenyl)-amide

4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide

Thiophene-3-carboxylic acid (4-amino-phenyl)-amide

5-Chloro-furan-2-carboxylic acid (4-amino-phenyl)-amide

5-Nitro-furan-2-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-2-thiophen-2-yl-acetamide

3-Methyl-furan-2-carboxylic acid (4-amino-phenyl)-amide

5-Bromo-furan-2-carboxylic acid (4-amino-phenyl)-amide

4-Bromo-furan-2-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-nicotinamide

N-(4-Aminophenyl)-3-furancarboxamide

4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide

Acetic acid 3-(4-amino-phenylcarbamoyl)-phenyl ester

Benzo[1,3]dioxole-4-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-3-(2-dimethylamino-ethoxy)-benzamide

N-(4-Amino-phenyl)-3-trifluoromethoxy-benzamide

N-(4-Amino-phenyl)-3-(2-morpholin-4-yl-ethoxy)-benzamide

(4-Amino-phenyl)-carbamic acid hexyl ester

Furan-2-carboxylic acid (4-amino-phenyl)-amide

(4-Amino-phenyl)-carbamic acid phenyl ester

Hexanoic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-acrylamide

N-(4-Amino-phenyl)-2-methoxy-acetamide

4-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide

5-tert-Butyl-furan-2-carboxylic acid (4-amino-phenyl)-amide

3-Chloro-4-methanesulfinyl-phenylamine

5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid (4-amino-phenyl)-amide

2-(4-Amino-2-chloro-phenyl)-ethanol

(4-Amino-2-chloro-phenyl)-carbamic acid 2-piperidin-1-yl-ethyl ester

5-Chloro-N,N-dimethyl-benzene-1,3-diamine

3-(2-Methyl-butyl)-5-trifluoromethyl-phenylamine

3-Isobutyl-5-trifluoromethyl-phenylamine

Furan-2-carboxylic acid (4-aminomethyl-phenyl)-amide

N-(4-Aminomethyl-phenyl)-2-fluoro-benzamide

[1,2,3]Thiadiazole-4-carboxylic acid (4-aminomethyl-phenyl)-amide

N-(4-Aminomethyl-phenyl)-2,6-difluoro-benzamide

Oxazole-4-carboxylic acid (4-amino-phenyl)-amide

N-(4-Amino-phenyl)-3-chloro-benzamide

N-(4-Amino-phenyl)-4-chloro-benzamide

Acetic acid 4-(4-amino-phenylcarbamoyl)-phenyl ester

N-(4-Amino-phenyl)-4-dimethylamino-benzamide

1-(4-Amino-phenyl)-3-(3,5-bis-trifluoromethyl-phenyl)-thiourea

N-(4-Amino-phenyl)-2-iodo-benzamide

N-(4-Amino-phenyl)-3-trifluoromethyl-benzamide

EXAMPLE 16 METHOD 3B 1-(4-Amino-2-chloro-phenyl)-ethanol

A 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (5.7 mL)is added to [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid2-trimethylsilanyl-ethyl ester (0.5 g) and the mixture is stirred atroom temperature for approximately 3.5 hours. The solution is thenconcentrated under reduced pressure, dissolved in a 1:1 mixture of ethylacetate and hexanes, washed successively with water then saturatedaqueous sodium chloride, and dried over anhydrous magnesium sulfate.Removal of the solvent under reduced pressure followed by chromatographyover silica gel (40% ethyl acetate in hexanes is used as the eluant)provides the product as an amber oil.

EXAMPLE 17 METHOD 3C N-(4-Amino-3-cyanophenyl)-2-fluoro-benzamide

Potassium carbonate (5.0 g) is added to a solution ofN-[3-cyano-4-(2,2,2-trifluoroacetyl-amino)-phenyl]-2-fluoro-benzamide(2.5 g) in methanol (270 mL) and water (16 mL) and the mixture isrefluxed overnight. After removing the solvent under reduced pressure,the residue is suspended in water and extracted with dichloromethane.The organic extracts are pooled, washed with water and then saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to provide the desiredcompound as a white solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N-(4-Amino-phenyl)-2-methanesulfinyl-benzamide

N-(4-Amino-3-cyano-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-3-cyano-phenyl)-amide

N-(4-Amino-3-cyano-phenyl)-acetamide

Furan-2-carboxylic acid (4-amino-3-trifluoromethyl-phenyl)-amide

N-(4-Amino-3-methoxy-phenyl)-acetamide

N-(4-Amino-3-methoxy-phenyl)-2-fluoro-benzamide

Furan-2-carboxylic acid (4-amino-3-methoxy-phenyl)-amide

EXAMPLE 17 METHOD 4A 2-Chloro-1-cyclohexyloxy-4-nitro-benzene

Cylcohexanol (2.9 g) in dimethylsulfoxide (20 mL) is added slowly to aflask containing potassium hydride (0.90 g, pre-washed three times withhexanes) under an atmosphere of argon and the solution is stirred forabout 1 hour at room temperature. A solution of3-chloro-4-fluoro-nitrobenzene (1 g) in dimethylsulfoxide (10 mL) isadded and the resulting dark red colored solution is then heated forthree hours to approximately 100 degrees. The reaction mixture is thencooled, diluted with diethyl ether (300 mL), and washed successivelywith saturated aqueous ammonium chloride, three times with water, thenwith saturated aqueous sodium chloride. The organic layer is then driedover anhydrous magnesium sulfate, the solvent is removed under reducedpressure, and the resulting oil is chromatographed over silica gel (5%ethyl acetate in hexanes is used as the eluant) to provide the desiredproduct as an orange solid.

EXAMPLE 18 METHOD 4C(2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-pyrrolidin-3-yl)-amine

3-Chloro-4-fluoronitrobenzene (1.0 g) andN,N′-dimethyl-3-aminopyrrolidine (1.72 g) are combined and stirred forapproximately 24 hours. The mixture is then diluted with ethyl acetate,washed twice with water and once with saturated sodium chloride, anddried over anhydrous sodium sulfate. After removal of the solvent underreduced pressure the residue is chromatographed over silica gel (pureethyl acetate followed by pure methanol is used as the eluants) toprovide the desired product as a yellow oil. p Using the above procedureand appropriate starting materials the following compounds wereprepared:

(2-Chloro-4-nitro-phenyl)-dipropyl-amine

1-(2-Chloro-4-nitro-phenyl)-piperidine

1-(2-Chloro-4-nitro-phenyl)-pyrrolidine

(2-Chloro-4-nitro-phenyl)-cyclohexyl-methyl-amine

Benzyl-(2-chloro-4-nitro-phenyl)-amine

(2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-piperidin-4-yl)-amine

(2-Chloro-4-nitro-phenyl)-cyclohexyl-ethyl-amine

(2-Chloro-4-nitro-phenyl)-cyclohexyl-amine

(2-Chloro-4-nitro-phenyl)-methyl-(1-methyl-pyrrolidin-3-yl)-amine

(1-Benzyl-pyrrolidin-3-yl)-(2-chloro-4-nitro-phenyl)-methyl-amine

(2-Chloro-4-nitro-phenyl)-cyclopentyl-methyl-amine

1-(2-Chloro-4-nitro-phenyl)-decahydro-quinoline

Allyl-(2-chloro-4-nitro-phenyl)-cyclohexyl-amine

2-[(2-Chloro-4-nitro-phenyl)-(2-hydroxy-ethyl)-amino]-ethanol

(2-Chloro-4-nitro-phenyl)-isobutyl-methyl-amine

(2-Chloro-4-nitro-phenyl)-hexyl-methyl-amine

2-[(2-Chloro-4-nitro-phenyl)-methyl-amino]-ethanol

N-(2-Chloro-4-nitro-phenyl)-N,N′,N′-trimethyl-ethane-1,2-diamine

N-(2-Chloro-4-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine

(1(-Benzyl-piperidin-4-yl)-(2-chloro-4-nitro-phenyl)-amine

N-(2-Chloro-4-nitro-phenyl)-N′,N′-dimethyl-ethane-1,2-diamine

N-(2-Chloro-4-nitro-phenyl)-N′,N′-dimethyl-propane-1,3-diamine

(2-Chloro-4-nitro-phenyl)-(2-methoxy-ethyl)-methyl-amine

(1-Benzyl-pyrrolidin-3-yl)-(2-chloro-4-nitro-phenyl)-amine

4-Piperidin-1-yl-3-trifluoromethyl-benzonitrile

4-Dimethylamino-3-trifluoromethyl-benzonitrile

4-(4-Methyl-piperazin-1-yl)-3-trifluoromethyl-benzonitrile

EXAMPLE 19 METHOD 4E Butyl-(2-chloro-4-nitro-phenyl)thioether

A solution of 3-chloro-4-fluoro-nitrobenzene (5.0 g) and sodium sulfide(2.5 g) in N,N-dimethylformamide (30 mL) is stirred at room temperaturefor 1 hour and then treated with 1-iodobutane (12.6 g). The solvent isthen removed under reduced pressure and the resulting residue is treatedwith ethyl acetate and hexanes to precipitate the inorganic salts. Thesolids are removed by filtration and the filtrate is reduced underreduced pressure. The resulting residue is then passed through hydrousmagnesium silicate using dichloromethane as the eluent to provide thedesired compound as a yellow solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

1-Butylsulfanyl-2-chloro-4-nitro-benzene

2-Chloro-1-cyclohexylsulfanyl-4-nitro-benzene

2-Chloro-1-ethylsulfanyl-4-nitro-benzene

EXAMPLE 20 METHOD 4F (4-Chloro-5-methoxy-2-nitro-phenyl)-dimethyl-amine

To a solution of trifluoro-methanesulfonic acid4-chloro-5-methoxy-2-nitro-phenyl ester (1.0 g) in tetrahydrofuran (2.0mL) is added dimethylamine (4.0 mL of a 40% aqueous solution) and themixture is stirred at room temperature for approximately 15 hours. Thesolution is then concentrated under reduced pressure and the residue isdissolved in ethyl acetate and then washed with water. The aqueous layeris extracted once with ethyl acetate and the combined organic layers arewashed with saturated aqueous sodium chloride and dried over anhydroussodium sulfate. The solvent is removed by evaporation under reducedpressure and the residue is triturated with hexanes to provide thedesired product as a colorless solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

(4-Chloro-2-nitro-phenyl)-dimethyl-amine

4-(4-Chloro-5-methoxy-2-nitro-phenyl)-morpholine

(4-Chloro-5-methoxy-2-nitro-phenyl)-dimethyl-amine

1-(4-Chloro-5-methoxy-2-nitro-phenyl)-piperidine

1-(4-Chloro-5-methoxy-2-nitro-phenyl)-pyrrolidine

Benzyl-(4-chloro-5-methoxy-2-nitro-phenyl)-amine

(2-Chloro-6-nitro-phenyl)-dimethyl-amine

EXAMPLE 21 METHOD 4G (2-Chloro-4-nitro-phenyl)-methyl-phenyl-amine

n-Butyl lithium (12.3 mL of a 2.5 M solution in hexanes) is addeddropwise to a solution of N-methyl aniline (3.0 g) in tetrahydrofuran(75 mL) at 0° C. The mixture is allowed to warm slowly to roomtemperature and is then re-cooled to 0° C. and added by cannula to asolution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35mL) that is kept at −78° C. Following the addition, the reaction mixtureis permitted to warm to room temperature over the course of 1 hour, andis then concentrated under reduced pressure, quenched by addition ofsaturated aqueous ammonium chloride, and extracted three times withethyl acetate. The pooled organic layers are washed three times with 5%aqueous hydrochloric acid, once with water, once with saturated aqueoussodium bicarbonate, once with saturated aqueous sodium chloride, andthen dried over anhydrous magnesium sulfate. Following removal of thesolvent under reduced pressure the residue is chromatographed oversilica gel (5% diethyl ether in hexanes is used as the eluant) toprovide the desired product as a clear colorless oil.

EXAMPLE 22 METHOD 4H 2,6-Dichloro-4-nitrophenol

3,4,5-Trichloronitrobenzene (14.86 g) is added to a solution ofpotassium phenoxide (8.66 g) in diethylene glycol (66 mL) and themixture is heated to 160° C. for approximately 15 hours. The resultingdark brown solution is cooled to room temperature, poured onto 100 mLcold water, and extracted twice with diethyl ether. The pooled organicextracts are washed with water, 10% aqueous sodium hydroxide, and thendried over anhydrous magnesium sulfate. Following removal of the solventunder reduced pressure the resulting oil is distilled in a Kugelrohrapparatus to provide a yellow oil that solidifies on standing.Recrystallization from ethanol-water provides the desired product as apale yellow solid.

EXAMPLE 23 METHOD 5A (3,5-Dichloro-4-ethoxy-phenyl)-carbamic acidtert-butyl ester

To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acidtert-butyl ester (1.0 g) and potassium carbonate (1.0 g) in acetone (18mL) is added ethyl iodide (0.36 mL) and the mixture is stirred forapproximately 15 hours at room temperature. The solution is thenfiltered, concentrated under reduced pressure, and partitioned betweenethyl acetate and water. The separated aqueous layer is furtherextracted twice with ethyl acetate, and the pooled organic extracts arewashed-successively with 10% aqueous sodium hydroxide, with water, andthen dried over anhydrous sodium sulfate. Evaporation of the solventunder reduced pressure gave the desired product as a tan solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

(3,5-Dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester

(4-Butoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester

(4-Benzyloxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester

(4-Carbamoylmethoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester

[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-carbamic acid tert-butylester

(4-tert-Butoxycarbonylamino-2,6-dichloro-phenoxy)-acetic acid methylester

3-Butoxy-benzoic acid methyl ester

3-tert-Butoxycarbonylmethoxy-benzoic acid methyl ester

3-Carbamoylmethoxy-benzoic acid methyl ester

[4-(3-Carbamoylmethoxy-benzoylamino)-phenyl]-carbamic acid tert-butylester

(4-[3-(2-Chloro-ethoxy)-benzoylamino]-phenyl}-carbamic acid tert-butylester

EXAMPLE 24 METHOD 5C (2,6-Dichloro-4-nitro-phenoxy)-acetic acidtert-butyl ester

To a solution of 2,6-dichloro-4-nitrophenol (2.5 g) and potassiumcarbonate (3.3 g) in dimethyl-formamide (50 mL) is addedtert-butyl-bromoacetate (10 mL) and the mixture is stirred at roomtemperature for two days. The solution is then poured into 500 mL water,extracted three times with hexanes, and the pooled organic extracts arewashed with saturated aqueous ammonium chloride and then dried overanhydrous magnesium sulfate. Evaporation of the solvent under reducedpressure followed by trituration of the resulting oil with hexanesprovides the desired product as a white solid.

Using the above procedure and starting materials the following compoundswere prepared:

3-Dimethylamino-1-(4-nitro-phenyl)-propenone

2-Chloro-1-isopropoxy-4-nitro-benzene

1,3-Dichloro-2-methoxy-4-methyl-5-nitro-benzene

1-Chloro-4-ethoxy-2-methoxy-5-nitro-benzene

1-Butoxy-4-chloro-5-methoxy-2-nitro-benzene

1-Chloro-2-methoxy-5-nitro-4-(phenylmethoxy)benzene (CA name)

1-Chloro-4-methoxy-5-nitro-2-(phenylmethoxy)benzene (CA name)

(2,6-Dichloro-4-nitro-phenoxy)-acetic acid tert-butyl ester

(2,6-Dichloro-4-nitro-phenoxy)-acetonitrile

1-Chloro-4-methoxy-2-methyl-5-nitro-benzene

2-(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetamide

2-(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetamide

(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetonitrile

(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetonitrile

4-(2-Chloro-5-methoxy-4-nitro-phenoxy)-butyronitrile

2-(4-Chloro-5-methoxy-2-nitro-phenoxy)-ethanol

2-(2-Chloro-5-methoxy-4-nitro-phenoxy)-ethanol

(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid tert-butyl ester

(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid methyl ester

(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetic acid methyl ester

(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetic acid tert-butyl ester

(2-Chloro-4-nitro-phenoxy)-acetonitrile

1-Butoxy-2-chloro-4-nitro-benzene

2-Chloro-4-nitro-1-(2,2,2-trifluoro-ethoxy)-benzene

2-Chloro-4-nitro-1-propoxy-benzene

2-Chloro-1-ethoxy-4-nitro-benzene

1,3-Diiodo-2,4-dimethoxy-5-nitro-benzene

1,3-Dibromo-2,4-dimethoxy-5-nitro-benzene

3-Chloro-2,4-dimethoxy-nitrobenzene

EXAMPLE 25 METHOD 5E [3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamicacid tert-butyl ester

To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acidtert-butyl ester (1.0 g) and potassium carbonate (0.55 g) in toluene (20mL) is added ethylene carbonate (1.6 g) and the mixture is heated toreflux for 3 hours. To the cooled reaction mixture is added 2.5 Maqueous sodium hydroxide (50 mL), and the separated organic layer isthen washed successively with water, then saturated aqueous sodiumchloride, and then dried over anhydrous sodium sulfate. The solvent isthen removed by evaporation under reduced pressure and the resultingresidue is chromatographed over silica gel (30% ethyl acetate in hexanesis used as the eluant) to provide the desired product as a white foam.

EXAMPLE 26 METHOD 6 3-(2-Chloro-4-nitro-phenoxy)-1-methyl-pyrrolidine

To a solution of 2-chloro-4-nitrophenol (2.0 g) in tetrahydrofuran (60mL) is added 1-methyl-3-pyrrolidinol (2.3 g), triphenyl phosphine (6.0g), and diethylazodicarboxylate (3.6 mL) and the mixture is stirred atroom temperature under an atmosphere of argon for 1.5 hours. Thesolution is then concentrated under reduced pressure, diluted with ethylacetate, washed successively with 10% aqueous sodium hydroxide, water,saturated aqueous sodium chloride, and dried over anhydrous magnesiumsulfate. The solvent is removed by evaporation under reduced pressureand the residue is chromatographed over silica gel (ethyl acetate then10% methanol in dichloromethane is used as the eluant). Pooled productfractions are then recrystallized from hexanes to provide the desiredproduct as a yellow solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

4-(2-Chloro-4-nitro-phenoxy)-1-methyl-piperidine

3-(2-Chloro-4-nitro-phenoxy)-1-methyl-pyrrolidine

[2-(2-Chloro-4-nitro-phenoxy)-ethyl]-dimethyl-amine

[3-(2-Chloro-4-nitro-phenoxy)-propyl]-dimethyl-amine

EXAMPLE 27 METHOD 7A 2-Chloro-3-methoxy-6-nitro-phenol and2,4-Dichloro-3-methoxy-6-nitro-phenol

To a flask containing 3-methoxy-6-nitro-phenol (0.5 g) is added aqueoussodium hypochlorite (5.25% aqueous solution, 21 mL) and the mixture isstirred at room temperature for approximately 24 hours. The mixture isthen cooled in an ice-bath, acidified by addition of concentratedhydrochloric acid, then extracted twice with ethyl acetate. Theseorganic extracts are dried over anhydrous magnesium sulfate, the solventis removed by evaporation under reduced pressure, and the residue ischromatographed over silca gel (15% acetone in hexanes is used as theeluant) to provide both the mono- and di-chlorinated products as yellowsolids. P Using the above procedure and appropriate starting materialsthe following compounds were prepared:

3-Chloro-2-hydroxy-4-methoxy-nitrobenzene

3,5-Dichloro-2-hydroxy-4-methoxy-nitrobenzene

EXAMPLE 28 METHOD 7B 2,4-Dichloro-3-methyl-6-nitro-phenol

To a solution of 3-methyl-4-nitro-phenol (5.0 g) in water (150 mL) isadded aqueous sodium hypochlorite (5.25% aqueous solution, 230 mL) andthe mixture is stirred at room temperature for approximately 15 hours.Additional aqueous sodium hypochlorite (5.25% aqueous solution, 230 mL)is added and the mixture is permitted to stir at room temperature for2.5 days. The mixture is then cooled in an ice-bath, acidified byaddition of concentrated hydrochloric acid, then extracted twice withethyl acetate. These organic extracts are dried over anhydrous magnesiumsulfate, the solvent is removed by evaporation under reduced pressure,and the residue is chromatographed over silca gel (ethyl acetate is usedas the eluant) to provide the desired product as a yellow solid. Ananalytically pure sample is obtained by a single recrystallization fromchloroform.

EXAMPLE 29 METHOD 7C 1-Bromo-2,4-dimethoxy-5-nitro-benzene

To a solution of 2,-dimethoxy-nitrobenzene (0.50 g) in chloroform (3 mL)is added dropwise a solution of bromine (0.23 g) in chloroform (1 mL)and the mixture is allowed to stir at room temperature for approximately15 hours. Additional bromine (0.15 g) in chloroform (1 mL) is added andthe reaction is stirred for an additional 4 hours. The mixture is thenpoured onto 5% aqueous sodium bisulfite and then extracted withchloroform. Pooled organic extracts are then washed successively with 5%aqueous sodium bisulfite then saturated sodium chloride, and then driedover anhydrous sodium sulfate. Removal of the solvent under reducedpressure and recrystallization of the residue from toluene provides thedesired product as a yellow solid.

EXAMPLE 30 METHOD 7D 2,4-Dibromo-3-methoxy-6-nitro-phenol

To a solution of 5-methoxy-2-nitro-phenol (0.25 g) and silvertrifluoroacetate (0.49 g) in glacial acetic acid (3 mL) is addeddropwise a solution of bromine (1.42 g) in glacial acetic acid (3 mL)and the mixture is stirred at room temperature for approximately 24hours. The solution is then partitioned between ethyl acetate and water,and the organic layer is washed successively three times with 5% aqueoussodium bisulfite, three times with saturated aqueous sodium bicarbonate,and once with saturated aqueous sodium chloride. The organic layer isthen dried over anhydrous magnesium sulfate and the solvent is removedunder reduced pressure. The residue is chromatographed over silica gel(20% ethyl acetate in hexanes is used as the eluant) then recrystallizedfrom chloroform to provide the desired dibrominated product as an orangesolid.

EXAMPLE 31 METHOD 7E 1-Iodo-2,4-dimethoxy-5-nitro-benzene

To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in glacial aceticacid (30 mL) is added benzyltrimethylammonium dichloroiodate (1.90 g)and anhydrous zinc chloride (1.0 g) and the mixture is stirred at roomtemperature under an atmosphere of argon. Additionalbenzyltrimethylammonium dichloroiodate (0.4 g) is added after 5 hoursand again after 24 hours. Additional zinc chloride (0.5 g) and glacialacetic acid (15 mL) is added after 24 hours. The mixture is permitted tostir at room temperature for 3 days and is then filtered, diluted with5% aqueous sodium bisulfite, and extracted three times with ethylacetate. These pooled organic extracts are washed successively with 5%aqueous sodium bisulfite, saturated aqueous sodium chloride, then driedover anhydrous magnesium sulfate. After removal of the solvent underreduced pressure the residue is triturated with hexanes to provide thedesired product as a pale yellow solid.

EXAMPLE 32 METHOD 7F 2,4-Diiodo-3-methoxy-6-nitro-phenol

To a solution of 5-methoxy-2-nitro-phenol (0.25 g) in dichloromethane(15 mL) and methanol (6 mL) is added benzyltrimethylammoniumdichloroiodate (1.08 g) and sodium bicarbonate (0.85 g) and the mixtureis allowed to stir at room temperature for 24 hours. The solution isthen filtered, the filtrate is concentrated under reduced pressure, theresidue is dissolved in ethyl acetate and then washed successively with5% aqueous sodium bicarbonate, 5% aqueous sodium bisulfite, andsaturated aqueous sodium chloride. After drying over anhydrous magnesiumsulfate the solvent is removed by evaporation under reduced pressure andthe residue is recrystallized from toluene to provide the desiredproduct as yellow needles.

EXAMPLE 33 METHOD 7G 1-Fluoro-2,4-dimethoxy-5-nitro-benzene

To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in tetrachloroethane(10 mL) is added 3,5-dichloro-1-fluoro-pyridinium triflate (85%, 5.07 g)and the mixture is heated to 120° C. for 5 hours. Additional3,5-dichloro-1-fluoro-pyridinium triflate (85%, 0.25 g) is added andheating is continued for 1 hour. The solution is then cooled to roomtemperature and passed over a column of silica gel (hexanes followed by30% ethyl acetate in hexanes is used as the eluant). Product containingfractions are combined, evaporated under reduced pressure, and theresidue is crystallized from hexanes to provide the desired product as atan solid.

EXAMPLE 34 METHOD 8 3-Chloro-4-trifluoromethyl-nitrobenzene

A solution of 3-chloro-4-iodo-nitrobenzene (2.26 g),trimethyl(trifluoromethyl)silane (5.68 g), copper(I) iodide (2.28 g),and potassium fluoride (0.56 g) in N,N-dimethylformamide (8 mL) isheated in a sealed tube to 80° C. for 40 hours. The solution is thencooled, diluted with diethyl ether, filtered through diatomaceous earth,and the filtrate is washed successively with water, saturated aqueoussodium chloride, and then dried over anhydrous sodium sulfate. Thesolvent is removed under reduced pressure and the residue ischromatographed over silica gel (1% diethyl ether in hexanes followed by10% ethyl acetate in hexanes is used as the eluant) to provided thedesired product as a colorless oil.

EXAMPLE 35 METHOD 9 (3-Chloro-4-methanesulfinyl-phenyl)-carbamic acidtert-butyl ester

To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acid tert-butylester (0.89 g) in dichloromethane (15 mL) at 0° C. is added a solutionof dimethyldioxirane (˜0.11 M in acetone, 34 mL) and the mixture isstirred at 0° C. for 1 hour. The solvent is removed under reducedpressure and the residue is dissolved in dichloromethane, washed withsaturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. Removal of the solvent under reduced pressure gavethe desired product as an orange foam.

EXAMPLE 36 METHOD 9B [4-(2-Methylsulfinyl-benzoylamino)-phenyl]-carbamicacid tert-butyl ester

To a solution of2-methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide(234 mg) is added a saturated solution of sodium periodate (5 mL) andthe mixture is stirred for 12 hours. The purple mixture is poured intowater, extracted with ethyl acetate, dried over anhydrous potassiumcarbonate and evaporated to yield a red solid, 101 mg.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[4-(2-Methanesulfinyl-benzoylamino)-phenyl]-carbamic acid tert-butylester

2-Methanesulfinyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide

EXAMPLE 37 METHOD 10 (3-Chloro-4methanesulfonyl-phenyl)-carbamic acidtert-butyl ester

To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acid tert-butylester (0.90 g) in dichloromethane (30 mL) at 0° C. is added a solutionof dimethyldioxirane (˜0.11 M in acetone, 80 mL) and the mixture isstirred at 0° C. for 1 hour. The solvent is removed under reducedpressure and the residue is dissolved in dichloromethane, washed withsaturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. Removal of the solvent under reduced pressure givesthe desired product as an orange foam.

EXAMPLE 38 METHOD 11 3-Chloro-4-vinyl-phenylamine

To a deoxygenated solution of 3-chloro-4-iodo-aniline (6.95 g),triphenyl arsine (0.67 g), and tris(dibenzylideneacetone)palladium(O)(0.50 g) in tetrahydrofuran (120 mL) at 50° C. is added tributylvinyltin(10 g) and the mixture is stirred for approximately 15 hours at 50° C.under an atmosphere of argon. The reaction is then cooled, filteredthrough diatomaceous earth, and the filtrate is evaporated to drynessunder reduced pressure. The residue is dissolved in hexanes and thenextracted three times with 5% aqueous hydrochloric acid. These aqueousacidic extracts are then basified with solid potassium carbonate andextracted three times with ethyl acetate. These pooled organic extractsare then washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, and the solvent is removed under reducedpressure. The resulting residue is chromatographed over silica gel(hexanes and then 10% ethyl acetate in hexanes is used as the eluant) toprovide the desired product as an amber oil.

EXAMPLE 39 METHOD 12 [3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid2-trimethylsilanyl-ethyl ester

(3-Chloro-4-vinyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester(2.6 g) is added to a solution of mercuric acetate (3.48 g) in water (7mL) and tetrahydrofuran (5.25 mL) and the mixture is stirred forapproximately 15 hours. 3N Aqueous sodium hydroxide (8.7 mL) and a 0.5 Msolution of sodium borohydride in 3N aqueous sodium hydroxide (8.7 mL)are then added and stirring is continued for 6 hours. The solution isthen saturated with sodium chloride and extracted with ethyl acetate.These organic extracts are then washed with saturated aqueous sodiumchloride and dried over anhydrous sodium sulfate.

Following removal of the solvent under reduced pressure the residue ischromatographed over silica gel (20% ethyl acetate in hexanes is used asthe eluant) to provide the desired product as a white solid.

EXAMPLE 40 METHOD 13 [3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-carbamic acidtert-butyl ester

To a stirring suspension of sodium borohydride (0.45 g) intetrahydrofuran (13 mL) at 0° C. is added glacial acetic acid (0.75 mL)and the mixture is stirred at 0° C. for 1 hour. The solution is thenwarmed to room temperature and (3-chloro-4-vinyl-phenyl)-carbamic acid2-trimethylsilanyl-ethyl ester (1.0 g) is added. The reaction is stirredat room temperature for approximately 15 hours and then heated to refluxfor approximately 20 hours. The mixture is then cooled and solutions of5 N aqueous sodium hydroxide (0.80 mL) and 30% aqueous hydrogen peroxide(0.56 mL) are added. After stirring for an additional 15 hours thelayers are separated, the aqueous layer is extracted three times withdiethyl ether, and these organic extracts are dried over anhydrousmagnesium sulfate. Following removal of the solvent under reducedpressure the residue is chromatographed over silica gel (40% ethylacetate in hexanes is used as the eluant) to provide the desired productas an amber oil.

EXAMPLE 41 METHOD 14 [4-(1-Azido-ethyl)-3-chloro-phenyl]-carbamic acid2-trimethylsilanyl-ethyl ester

To a solution of [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid2-trimethylsilanyl-ethyl ester (1.25 g) in tetrahydrofuran (20 mL) at 0°C. under an atmosphere of argon is added triphenyl-phosphine (2.6 g),hydrazoic acid (approximately 2.5 molar equivalents in dichloromethane,prepared by the method of Fieser and Fieser, Reagents for OrganicSynthesis, Vol. 1, pg. 446; Wiley, New York) and diethylazodicarboxylate (1.72 g). After approximately 10 minutes the solvent isremoved under reduced pressure and the residue is chromatographed oversilica gel (5% ethyl acetate in hexanes is used as the eluant) toprovide the desired product as a colorless oil.

EXAMPLE 42 METHOD 15[3-Chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acidtert-butyl ester

To a deoxygenated solution of (3-chloro-4-iodo-phenyl)-carbamic acidtert-butyl ester (10.0 g) in triethylamine (120 ml) is added1-dimethylamino-2-propyne (2.82 g),bis(triphenyl-phosphine)palladium(II) chloride (0.4 g), and cuprousiodide (0.054 g). The mixture is stirred at room temperature under anatmosphere of argon for approximately 6 hours and is then heated briefly(ca. 10 minutes) to 60° C. The reaction mixture is then cooled, filteredthrough diatomaceous earth, and the solvent is removed by evaporationunder reduced pressure. The residue is dissolved in ethyl acetate,washed three times with water, once with saturated aqueous sodiumchloride, and dried over anhydrous magnesium sulfate. The solvent isremoved by evaporation under reduced pressure, and the residue ischromatographed over silica gel (80% ethyl acetate in hexanes is used asthe eluant) to give the purified product as an amber oil that solidifiedon standing.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[3-Chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acidtert-butyl ester

[3-(4-Methoxy-phenyl)-prop-2-ynyl]-dimethyl-amine

4-(3-Dimethylamino-prop-1-ynyl)-benzonitrile

Dimethyl-[3-(4-nitro-phenyl)-prop-2-ynyl]-amine

EXAMPLE 43 METHOD 16[3-Chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert-butylester

To an ice cold solution of[3-chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acidtert-butyl ester (4.0 g) in dichloromethane (30 ml) is added in smallportions 3-chloroperoxybenzoic acid (2.34 g). After the reaction isstirred at 0° C. for 20 minutes, the mixture is passed over twentyweight equivalents of basic alumina (Brockmann Grade I, 150 mesh) andthe N-oxide is eluted using a solution of 5% methanol indichloromethane. All fractions containing the desired amine N-oxide werecombined and evaporated to near dryness under reduced pressure. Theresidue is treated successively three times with small portions ofmethanol (ca. 50 ml) followed by evaporation to near dryness underreduced pressure, and the volume of the solution is adjusted to 250 mLby addition of methanol. The methanolic solution of the N-oxide is thenheated to reflux for approximately 15 hours, then cooled, and thesolvent is evaporated to dryness under reduced pressure. The residue ispurified by chromatography over silica gel (80% ethyl acetate in hexanesis used as the eluant) to give the desired product as a pale yellowsolid.

EXAMPLE 44 METHOD 17 (3-Chloro-4-isoxazol-5-yl-phenyl)-carbamic acidtert-butyl ester

A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamicacid tert-butyl ester (270 mg) in dioxane (3 ml) is treated withhydroxylamine hydrochloride (122 mg) and the mixture is stirred at roomtemperature for 10 days. The mixture is diluted with ethyl acetate,washed successively with water, 5% aqueous sodium bicarbonate, saturatedaqueous sodium chloride, and then dried over anhydrous magnesiumsulfate. The solvent is removed by evaporation under reduced pressureand the resulting residue is chromatographed over silica gel (33% ethylacetate in hexanes is used as the eluant) to provide the desired productas a colorless solid.

EXAMPLE 45 METHOD 18 [3-Chloro-4-(1H-pyrazol-3-yl)-phenyl]-carbamic acidtert-butyl ester

A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamicacid tert-butyl ester (250 mg) in ethanol (1.25 ml) is treated withhydrazine hydrate (0.25 ml) and the mixture is stirred at roomtemperature for 3 hours. The mixture is then diluted with 30 mL ofdiethyl ether, washed three times with water, once with saturatedaqueous sodium chloride, and dried over anhydrous magnesium sulfate. Thesolvent is removed by evaporation under reduced pressure and theresulting residue is chromatographed over silica gel (67% ethyl acetatein hexanes is used as the eluant) to provide the desired product as anoil.

EXAMPLE 46 METHOD 19AN-(2-Chloro-4-nitrophenyl)-2-thiomorpholino-4-yl-acetamide

To a solution N-(chloroacetyl)-2-chloro-4-nitroaniline (3.80 g) intetrahydrofuran (50 mL) is added thiomorpholine (10 mL) and the solutionallowed to stand for 1 hour. This reaction mixture is poured into watera pale yellow solid is collected and then recrystallized from hot2-propanol to give a pale yellow crystalline solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

(4-{2-[Bis-(2-hydroxy-ethyl)-amino]-acetylamino}-phenyl)-carbamic acidtert-butyl ester

[4-(2-Dimethylamino-acetylamino)-phenyl]-carbamic acid tert-butyl ester

{4-[3-(2-Dimethylamino-ethoxy)-benzoylamino]-phenyl}-carbamic acidtert-butyl ester

{4-[3-(2-Morpholin-4-yl-ethoxy)-benzoylamino]-phenyl}-carbamic acidtert-butyl ester

N-(2-Chloro-4-nitro-phenyl)-2-dimethylamino-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-piperidin-1-yl-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-morpholin-4-yl-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-dipropylamino-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-thiomorpholin-4-yl-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-diethylamino-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-pyrrolidin-1-yl-acetamide

2-Azepan-1-yl-N-(2-chloro-4-nitro-phenyl)-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-(2-methyl-piperidin-1-yl)-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-(3-methyl-piperidin-1-yl)-acetamide

N-(2-Chloro-4-nitro-phenyl)-2-(4-methyl-piperidin-1-yl)-acetamide

EXAMPLE 47 METHOD 19BN-(2-Chloro-4-nitrophenyl)-2-(2-dimethylaminoethylsulfanyl)acetamide

To a solution of N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01 g) inN,N-dimethylformamide (100 mL) is added powdered sodium carbonate (6.0g) and 2-dimethylaminoethanethiol hydrochloride (6.0 g). The mixture isstirred for 1 hour at 25° C., poured into water and extracted into ethylacetate. The ethyl acetate solution is dried over anhydrous potassiumcarbonate and concentrated under reduced pressure to give an oil. Theoil is crystallized from toluene-hexanes (3:1) to yield a pale yellowcrystalline solid.

EXAMPLE 48 METHOD 20(4-tert-butoxycarbonylamino-2-chloro-phenyl)-carbamic acid2-piperidin-1-yl-ethyl ester

To a suspension of 1,1-carbonyl-di-(1,2,4)-triazole (4.0 g) indichloromethane (40 mL) is added a solution of (4-amino-3-chloro-phenyl)carbamic acid tert-butyl ester (5.0 g) in dichloromethane (45 mL)dropwise over 20 minutes. The reaction is stirred at room temperaturefor 30 minutes at which point a precipitate forms. To this mixture isadded piperidineethanol (6.6 mL) and tetra-hydrofuran (20 mL) is addedto maintain homogeneity. After heating at reflux overnight the reactionis cooled and then poured into water, the organic layer separated andthen washed with saturated aqueous sodium chloride. The solution isdried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to a crude oil that is purified by chromatography oversilica gel (5% methanol in dichloromethane is used as the eluant) togive the desired product as a white foam.

EXAMPLE 49 METHOD 21 5-Phenyl-[1,2,3]thiadiazole-4-carboxylic acidmethyl ester

A solution of ethyl benzoylacetate (1.1 g) in acetonitrile (10 mL) istreated with 4-methylbenzenesulfonyl azide (1.3 g) and triethylamine(1.6 g). After stirring overnight at room temperature, the reaction isconcentrated under reduced pressure and the resulting crude product isdissolved in ethyl acetate and washed with 1 N sodium hydroxide. Theorganic layer is then dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure to yield a yellow oil.

This oil is taken into dichloromethane and filtered through a pad ofhydrous magnesium silicate, eluting with dichloromethane to give thepartially purified diazoketone as a colorless oil. A sample of thediazoketone from above (1.2 g) is dissolved in toluene (25 mL) andtreated with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (2.8g) and the reaction is heated to reflux. After 3 hours, the reaction iscooled to room temperature, loaded onto a pad of silica gel and elutedwith dichloromethane. After removing the solvent under reduced pressure,the resulting oil is purified by chromatography over silica gel (30%diethyl ether in petroleum ether is used as the eluant) and thenrecrystallized from hexanes to give the desired product as pale yellowneedles.

Using the above procedure and appropriate starting materials thefollowing compound was prepared:

5-Phenyl-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester

5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid methyl ester

EXAMPLE 50 Ethyl benzoylacetate semicarbazide

Ethyl benzoylacetate (5.0 g) is dissolved in methanol (10 mL) and addedrapidly to a hot solution of semicarbazide hydrochloride (29 g) in water(130 mL). To this is added pyridine (4.1 g) and after heating to refluxfor 5 minutes, the reaction mixture is cooled to −20° C. overnight. Theresulting solid semicarbazone is collected by filtration, washed withwater and then diethyl ether to give the desired product as whitecrystals.

Using the above procedure and appropriate starting materials thefollowing compound was prepared:

Ethyl (Z)-3-[(aminocarbonyl)hydrazono]-4,4,4-trifluorobutanoate

3-[(Z)-2-(Aminocarbonyl)hydrazono]-3-phenylpropanoic acid ethyl ester

3-[(E)-2-(Aminocarbonyl)hydrazono]-3-(3-furyl)propanoic acid ethyl ster

EXAMPLE 51 5-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid ethyl ester

A solution of ethyl benzoylacetate semicarbazone (2.5 g) in neat thionylchloride (5 mL) is stirred at 0° C. for 1 hour. Dichloromethane is thenadded (25 mL), the excess thionyl chloride is destroyed slowly withsaturated aqueous sodium bicarbonate. The precipitate which forms onquenching is removed by filtration and the filtrate is extracted withdichloromethane. Pooled organic extracts are dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure.Chromatography over silica gel (50% hexanes in dichloromethane is usedas the eluant) affords the desired product as a colorless oil.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl ester

4-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid ethyl ester

4-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylic acid ethyl ester

EXAMPLE 52 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid

4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl ester (1.7 g) isdissolved in methanol (15 mL) and treated with 1N sodium hydroxide (16mL). After stirring at room temperature for 1 hour, the reaction istreated with concentrated hydrochloric acid (1.5 mL) and concentratedunder reduced pressure. The resulting turbid aqueous layer is extractedtwice with diethyl ether and the pooled organic layers are dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure to give the desired compound as a white powder.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

3-Ethoxycarbonylmethoxy-benzoic acid

5-Furan-3-yl-[1,2,3]thiadiazole-4-carboxylic acid

Thiazole-4-carboxylic acid

4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid

5-Methyl-[1,2,3]thiadiazole-4-carboxylic acid

EXAMPLE 53 METHOD 25 Trifluoro-methanesulfonic acid4-chloro-5-methoxy-2-nitro-phenyl ester

To a solution of 4-chloro-5-methoxy-2-nitro-phenol (6.5 g) indichloromethane (150 mL) at 0° C. under an atmosphere of argon is addedtriethylamine (10 g) and then a solution of trifluoro-methanesulfonicanhydride (13.5 g) in dichloromethane (30 mL). The solution is stirredat 0° C. for 10 minutes, and is then diluted with dichloromethane andwashed successively with saturated aqueous sodium bicarbonate andsaturated aqueous sodium chloride. After drying over anhydrous sodiumsulfate the solvent is removed by evaporation under reduced pressure andthe residue is dissolved in a solution of 20% dichloromethane in hexanesand passed through a short column of hydrous magnesium silicate (20%dichloromethane in hexanes is used as the eluant). Product containingfractions are pooled and the solvents removed by evaporation underreduced pressure to give the desired product as a yellow oil.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

Trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester

Trifluoro-methanesulfonic acid 4-chloro-2-nitro-phenyl ester

Trifluoro-methanesulfonic acid 2-chloro-6-nitro-phenyl ester

EXAMPLE 54 METHOD 26 [4-(3-Dimethylamino-benzoylamino)-phenyl]-carbamicacid t-butyl ester

A solution of [4-(3-amino-benzoylamino)-phenyl]-carbamic acid t-butylester (505 mg), sodium cyanoborohydride (250 mg), acetic acid (3 drops)and 40% aqueous formaldehyde (4 mL) in 1:2 tetrahydrofuran-methanol (15mL) is stirred for 15 minutes, and then poured into saturated aqueoussodium bicarbonate and extracted into ethyl acetate. The ethyl acetatesolution is dried over anhydrous potassium carbonate and concentratedunder reduced pressure to give a solid which is recrystallized fromacetonitrile to provide a pale pink crystalline solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[4-(3-Dimethylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester

(3-Bromo-5-trifluoromethyl-phenyl)-dimethyl-amine

N-(3-Chloro-5-dimethylamino-phenyl)-acetamide

EXAMPLE 55 METHOD 27 N-(4-Aminophenyl)-2-hydroxybenzamide

To a solution of 2-(4-aminophenylcarbamoyl) phenyl acetate (580 mg) inmethanol (10 mL) is added saturated sodium bicarbonate (2 mL) and water(3 mL). The mixture is heated at 80° C. for 30 minutes, then poured intohalf-saturated aqueous sodium chloride and extracted with ethyl acetate.The ethyl acetate solution is dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give an oil which is thentriturated with diethyl ether to provide the desired product as a whitesolid.

EXAMPLE 56 METHOD 28 [4-(3-(Hydroxybenzoylamino)phenyl}carbamic acidt-butyl ester

To a solution of of 3-(4-aminophenylcarbamoyl) phenyl acetate (4.34 g)in methanol (75 mL) is added 0.1 N aqueous sodium hydroxide (25 mL) andtetrahydrofuran (25 mL). This solution is heated at 40° C. for 30minutes, then cooled, poured into 1 M hydrochloric acid and extractedwith ethyl acetate. The ethyl acetate solution is dried over anhydroussodium sulfate and concentrated under reduced pressure to give a whitesolid, which is further purified by trituration with diethyl ether.

EXAMPLE 57 METHOD 29 N-(4-Aminophenyl)-2-hydroxymethylbenzamide

To a solution of N-(4-aminophenyl)phthalimide (332 mg) intetrahydrofuran (4 mL) is added lithium borohydride (1.0 g) and themixture is stirred for 1 hour at 25° C. The mixture is poured into waterand extracted into ethyl acetate. The ethyl acetate solution is driedover anhydrous sodium sulfate and concentrated under reduced pressure togive a white foam, which when triturated with diethyl ether provides thedesired product as a white powder.

EXAMPLE 58 METHOD 30 (3-Chloro-5-dimethylamino-phenyl)-carbamic acidtert-butyl ester

To a solution of (3-amino-5-chloro-phenyl)-carbamic acid tert-butylester (0.32 g) in toluene (10 mL) is added aqueous formaldehyde (37%,1.5 mL) then 10% palladium on carbon (0.50 g) and the mixture is stirredunder an atmosphere of hydrogen for approximately 15 hours. The solutionis then filtered through diatomaceous earth and the filtrate isconcentrated under reduced pressure. The residue is chromatographed oversilica gel (50% dichloromethane in hexanes is used as the eluant) toprovide the desired product as a white solid.

EXAMPLE 59 METHOD 35N-(4-{3-[3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide

To a solution of acetic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethylester (0.16 g) in a 1:1 mixture of tetrahydrofuran and methanol (2.5 mL)is added 1N aqueous sodium hydroxide (1 mL) and the mixture is stirredfor approximately 2 hours at room temperature. The solution is thenpoured into 2 M aqueous hydrochloric acid (3 mL), extracted into ethylacetate, and the extracts are dried over anhydrous sodium sulfate. Thesolvent is removed by evaporation under reduced pressure and the residueis triturated with diethyl ether to provide the desired product as awhite solid.

EXAMPLE 60 METHOD 36{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticacid

To a solution of{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticacid ethyl ester (0.29 g) in a 1:1 mixture of tetrahydrofuran andmethanol (4 mL) is added 1N aqueous sodium hydroxide (2 mL) and themixture is stirred for approximately 2 hours at room temperature. Thesolution is then poured into 2 M aqueous hydrochloric acid (5 mL),extracted into ethyl acetate, and the extracts are dried over anhydroussodium sulfate. The solvent is removed by evaporation under reducedpressure and the residue is triturated with diethyl ether to provide thedesired product as a white solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticacid

{2-[3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-phenoxy}-aceticacid

{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-aceticacid

EXAMPLE 61 METHOD 37 Benzoic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethylester

To an ice cooled solution ofN-(4-(3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido)-phenyl)-acetamide(0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is addedbenzoyl chloride (0.08 g) and the mixture is stirred at 0° C. for 1.5hours. The mixture is then diluted with ethyl acetate, washedsuccessively two times with 2% aqueous hydrochloric acid, once withsaturated aqueous sodium chloride, then dried over anhydrous sodiumsulfate. After removal of the solvent under reduced pressure the residueis chromatographed over silica gel (5% methanol in dichloromethane isused as the eluant) and product containing fractions are combined,evaporated under reduced pressure, and the residue is recrystallizedfrom acetone-hexanes to provide the desired product as a white powder.

EXAMPLE 62 METHOD 38 Methanesulfonic acid2-14-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethylester

To an ice cooled solution ofN-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide(0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is addedmethanesulfonyl chloride (0.11 g) and the solution is stirred at 0° C.for 45 minutes. The reaction mixture is then diluted with ethyl acetate,washed successively twice with 2% aqueous hydrochloric acid, once withsaturated aqueous sodium chloride, and then dried over anhydrousmagnesium sulfate. After removing the solvents by evaporation underreduced pressure the resulting residue is recrystallized fromacetone-hexanes to give the desired product as a white powder.

EXAMPLE 63 METHOD 39N-(4-{3-[3,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide

To a solution of methanesulfonic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichlorophenoxy}-ethylester (0.33 g) in tetrahydrofuran (6 mL) is added aqueous dimethyl-amine(8.8 M, 0.5 mL) and the mixture is stirred at room temperature for 5days. The reaction mixture is then diluted with ethyl acetate, thenwashed with saturated aqueous sodium chloride and dried over anhydrousmagnesium sulfate. After removal of the solvent under reduced pressurethe residue is chromatographed over silica gel (pure methanol is used asthe eluant). Pooled product containing fractions are evaporated underreduced pressure and the residue is recrystallized from acetonitrile toprovide the desired product as a white powder.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N-(4-{3-[3,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide

Benzoic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethylester

EXAMPLE 64 METHOD 40 Furan-2-carboxylic acid(4-{3-[4-(1-amino-ethyl)-3-chloro-phenyl]-thioureido)-phenyl}-amide

To a solution of tin(II) chloride dihydrate (0.25 g) in methanol (2.5mL) is added furan-2-carboxylic acid(4-{3-[4-(1-azido-ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-amide(0.22 g) and the solution is stirred for approximately 15 hours at roomtemperature. The solution is then diluted with ethyl acetate, washedsuccessively with saturated aqueous sodium bicarbonate then saturatedaqueous sodium chloride, then dried over anhydrous sodium sulfate. Afterremoval of the solvent by evaporation under reduced pressure the residueis chromatographed over silica gel (8% methanol in dichloromethanecontaining 1% triethylamine is used as the eluant) to provide thedesired product as a yellow solid.

EXAMPLE 65 METHOD 41 [1,2,3]Thiadiazole-4carboxylic acid(4-isothiocyanato-phenyl)-amide

To a ice cooled solution of 1,1′-thiocarbonyldiimidazole (7.28 g) intetrahydrofuran (50 mL) is added [1,2,3]-thiadiazole-4-carboxylic acid(4-amino-phenyl) amide (9.0 g) in tetrahydrofuran (100 mL). Afterapproximately one hour the solvent is removed by evaporation and theresidue is dissolved in ethyl acetate. Diethyl ether is added toprecipitate the crude product, which is then collected by filtration,dissolved in dichloromethane, and passed through a plug of hydrousmagnesium silicate. After removal of solvents, the residue isrecrystallized from ethyl acetate-hexanes to provide the desired productas a slightly yellow solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

2-Fluoro-N-(4-isothiocyanato-phenyl)-benzamide

Furan-2-carboxylic acid (4-isothiocyanato-phenyl)-amide

[1,2,3]Thiadiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide

Thiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide

EXAMPLE 66 METHOD 42 N,N-Dimethyl-5-trifluoromethyl-benzene-1,3-diamine

To a solution of 3-amino-5-bromo-benzotrifluoride (1.0 g) in degassed(argon) tetrahydrofuran (2 mL) is addedbis-(tri-o-tolylphosphino)palladium (0.15 g), a solution ofdimethylamine in tetra-hydrofuran (2M, 4.2 mL), and a solution oflithium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 10.4 mL). Thereaction mixture is heated in a sealed vessel to 100° C. forapproximately 2.5 hours to complete the reaction. The mixture is thencooled to room temperature, quenched by addition of water, and dilutedwith ethyl acetate. The product is extracted three times into 5% aqueoushydrochloric acid, and pooled acidic extracts are then basified withcooling by addition of 5N aqueous sodium hydroxide. This basic solutionis then extracted with ethyl acetate, and these pooled organic extractsare washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, and evaporated to dryness under reduced pressure. Theresulting residue is chromatographed over silica gel (20-30% ethylacetate in hexanes is used as the eluant) to provide the desired productas a slightly tinted solid.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

3-(4-Methyl-piperazin-1-yl)-5-trifluoromethyl-phenylamine

3-Morpholin-4-yl-5-trifluoromethyl-phenylamine

3-Piperidin-1-yl-5-trifluoromethyl-phenylamine

3-Pyrrolidin-1-yl-5-trifluoromethyl-phenylamine

N,N-Dimethyl-5-trifluoromethyl-benzene-1,3-diamine

N-Isobutyl-N-methyl-5-trifluoromethyl-benzene-1,3-diamine

N-Butyl-N-methyl-5-trifluoromethyl-benzene-1,3-diamine

EXAMPLE 67 METHOD 43 (3-Isobutyl-5-trifluoromethyl-phenyl)-carbamic Acidtert-butyl Ester

To a sealed tube containing tetrahydrofuran (5 mL) that is capped with arubber septum and cooled in a dry ice-acetone bath is bubbledisobutylene for about 5 minutes. A solution of9-borabicyclo[3.3.1]nonane in tetrahydrofuran (0.5 M, 11 mL) is added,the vessel is sealed with a teflon cap, slowly warmed to roomtemperature and kept at room temperature for approximately 2.5 hours.The mixture is then re-cooled in a dry ice-acetone bath, the teflon capis replaced by a rubber septum, and argon is bubbled through the mixturewith venting to removed the excess isobutylene. A solution of(3-bromo-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (1.7g) in tetrahydrofuran (12 mL) is added, followed by[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)chloride-dichlormethane complex (0.12 g), and then 3N aqueous sodiumhydroxide. The vessel is again sealed with the teflon cap and is thenheated to 65° C. for approximately 15 hours. The mixture is then cooledto room temperature, diluted with hexanes, washed with water, saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate, andevaporated under reduced pressure. The resulting oil is chromatographedover silica gel (5% ethyl acetate in hexanes is used as the eluant) toprovide the desired product as a white powder.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

[3-(2-Methyl-butyl)-5-trifluoromethyl-phenyl]-carbamic acid tert-butylester

(3-Isobutyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester

EXAMPLE 68 METHOD 44 2-(3,5-Dichloro-phenylsulfanyl)-ethylamine

To a solution of (3,5-dichlorophenylthio)acetonitrile (1.2 g) in 3.0 mLof ethylene glycol dimethyl ether is added 0.61 mL of 10M boranedimethyl sulfide complex and the mixture heated at reflux for 0.5 hours.The reaction is cooled in an ice bath and 2.0 mL of water and 2.0 mL ofconcentrated hydrochloric acid is added. This mixture is heated atreflux for 0.5 hr. The clear solution is then cooled and basified with5N sodium hydroxide and extracted with ether. The ether extract is driedover potassium carbonate, filtered and concentrated to give 1.0 g of acolorless oil.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

2-(3-Bromo-phenylsulfanyl)-ethylamine

2-(4-Bromo-phenoxy)-ethylamine

2-(4-Iodo-phenoxy)-ethylamine

2-(3,4-Dichloro-phenoxy)-ethylamine

2-(3-Chloro-phenylsulfanyl)-ethylamine

2-(3,4-Dichloro-phenylsulfanyl)-ethylamine

3-(4-Bromo-phenyl)-propylamine

2-(2-Fluoro-phenoxy)-ethylamine

2-(2-Chloro-phenoxy)-ethylamine

2-(3-Bromo-phenoxy)-ethylamine

2-(3-Fluoro-phenoxy)-ethylamine

2-(3-Iodo-phenoxy)-ethylamine

2-(3,5-Dichloro-phenylsulfanyl)-ethylamine

2-Phenylsulfanyl-ethylamine

1-(2-Chloro-phenyl)-ethylamine

EXAMPLE 69 METHOD 45 N-(1-Naphthalen-2-yl-ethyl)-formamide

A mixture of 2-acetylnaphthylene (3.0 g), ammonium formate (11.0 g),formic acid (3.3 mL), and formamide (3.5 mL) is heated at 190° C. for 3hours. The mixture is cooled, poured into water and extracted withether. The ether extract is dried with anhydrous potassium carbonate,filtered and concentrated to give a yellow oil, which is crystallizedfrom toluene-hexanes to give a white solid, 1.97 g.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

N-[1-(4-Fluoro-phenyl)-2-methyl-propyl]-formamide

N-(1-Naphthalen-2-yl-ethyl)-formamide

EXAMPLE 70 METHOD 46 1-(2-Naphthyl)ethylamine

A mixture of N-(1-naphthalen-2-yl-ethyl)-formamide (1.12 g), ethanol (10mL) and 5 N sodium hydroxide (10 mL) is heated at reflux for 1 hour. Thesolution is cooled, poured into water and extracted with ether. Theether solution is dried with anhydrous potassium carbonate, filtered andconcentrated to give the product (0.95 g) as a pale yellow oil.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

1-(3-Trifluoromethyl-phenyl)-ethylamine

1-(4-Fluoro-phenyl)-2-methyl-propylamine

[3-(1-Amino-ethyl)-phenyl]-dimethyl-amine

3-(1-Amino-ethyl)-benzonitrile

EXAMPLE 71 METHOD 47 1-(3-Trifluoromethyl-phenyl)-ethanoneO-methyl-oxime

Methoxylamine hydrochloride (2.33 g) is added to a solution of3′-(trifluoromethyl)-acetophenone (1.5 g) in ethanol (20 mL) andpyridine (2 mL). The solution is heated at reflux for 45 minutes. Thereaction mixture is then cooled, concentrated under reduced pressure andpartitioned between water and ethyl acetate. The aqueous layer isextracted with ethyl acetate. The combined organic layers are washedwith saturated aqueous sodium chloride, dried over anhydrous, magnesiumsulfate and concentrated under reduced pressure to give the desiredproduct as a colorless oil (1.61 g).

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

3,5-Bis-trifluoromethyl-benzaldehyde oxime

1-(4-Fluoro-phenyl)-propan-1-one O-methyl-oxime

1-(2-Chloro-phenyl)-ethanone O-methyl-oxime

1-(3-Bromo-phenyl)-ethanone O-methyl-oxime

1-(3-Chloro-phenyl)-ethanone O-methyl-oxime

1-p-Tolyl-ethanone O-methyl-oxime

1-(4-Fluoro-phenyl)-pentan-1-one O-methyl-oxime

1-(4-Fluoro-phenyl)-2-phenyl-ethanone O-methyl-oxime

1-o-Tolyl-ethanone O-methyl-oxime

1-m-Tolyl-ethanone O-methyl-oxime

1-(2-Fluoro-phenyl)-ethanone O-methyl-oxime

3-(1-Methoxyimino-ethyl)-benzonitrile

4-(1-Methoxyimino-ethyl)-benzonitrile

1-(4-Methoxy-phenyl)-ethanone O-methyl-oxime

1-(2-Methoxy-phenyl)-ethanone O-methyl-oxime

1-(4-Dimethylamino-phenyl)-ethanone O-methyl-oxime

1-(2-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime

1-(3-Methoxy-phenyl)-ethanone O-methyl-oxime

1-(3-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime

1-(4-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime

1-Furan-2-yl-ethanone O-methyl-oxime

1-Pyridin-4-yl-ethanone O-methyl-oxime

1-(1-Methyl-1H-pyrrol-2-yl)-ethanone O-methyl-oxime

1-Thiophen-3-yl-ethanone O-methyl-oxime

(4-Fluoro-phenyl)-phenyl-methanone O-methyl-oxime

1-(4-methoxyphenyl)ethanone O-methyloxime

1-(3-Chloro-4-methoxy-phenyl)-ethanone O-methyl-oxime

4-(1-Methoxyimino-ethyl)-benzenesulfonamide

4-(1-Methoxyimino-ethyl)-N,N-dimethyl-benzenesulfonamide

1-[4-(Piperidine-1-sulfonyl)-phenyl]-ethanone O-methyl-oxime

4-(1-Methoxyimino-ethyl)-N,N-dipropyl-benzenesulfonamide

2-Fluoro-N-[4-(1-methoxyimino-ethyl)-phenyl]-benzamide

1-(3,5-Bis-trifluoromethyl-phenyl)-ethanone O-methyl-oxime

1-[4-(1H-Imidazol-1-yl)phenyl]-1-ethanone, O-methyloxime

1-[4-(Trifluoromethyl)phenyl]-1-ethanone, O-methyloxime

1-[1,1′-Biphenyl]-4-yl-1-ethanone, O-methyloxime

1-(4-Methylphenyl)-1-ethanone, O-methyloxime

1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-[3,5-bis(trifluoromethyl)phenyl]ethanone O-benzyloxime

1-[4-chloro-3-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-[2-fluoro-4-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-[2-fluoro-5-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-(2,4-dichlorophenyl)ethanone O-methyloxime

1-(2,4-dimethylphenyl)ethanone O-methyloxime

1-[2,4-bis(trifluoromethyl)phenyl]ethanone O-methyloxime

1-(3-bromophenyl)ethanone O-methyloxime

1-(3-methylphenyl)ethanone O-methyloxime

1-[4-(4-morpholinyl)phenyl]ethanone O-methyloxime

1-(2-chloro-4-fluorophenyl)ethanone O-methyloxime

1-(4-bromo-2-fluorophenyl)ethanone O-methyloxime

1-(3,4-difluorophenyl)ethanone O-methyloxime

1-[3-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-[2-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-(2,4-difluorophenyl)ethanone O-methyloxime

1-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-(3,4-dichlorophenyl)ethanone O-methyloxime

1-[4-fluoro-2-(trifluoromethyl)phenyl]ethanone O-methyloxime

1-(3-chloro-4-fluorophenyl)ethanone O-methyloxime

1-(4-chloro-3-fluorophenyl)ethanone O-methyloxime

1-(2,5-difluorophenyl)ethanone O-methyloxime

1-(2-bromo-4-fluorophenyl)ethanone O-methyloxime

1-(3,4-dibromophenyl)ethanone O-methyloxime

1-(2-bromophenyl)ethanone O-methyloxime

EXAMPLE 72 METHOD 48 1-(2-Trifluoromethyl-phenyl)-ethylamine

Sodium borohydride (1.17 g) is added slowly to a flask containingzirconium tetrachloride (1.8 g) in tetrahydrofuran (27 mL). A solutionof 1-(2-trifluoromethyl-phenyl)-ethanone O-methyl-oxime (1.34 g) intetrahydrofuran (7.7 mL) is added and the resulting solution is stirredat 25° C. for 12 hours. The reaction mixture is then cooled to 0° C. andwater (16 mL) is slowly added. Excess ammonium hydroxide is added andthe solution is extracted twice with ethyl acetate. The organic portionis washed twice with 1N hydrochloric acid. The aqueous (acid) layer isbasified with sodium hydroxide and extracted twice with ethyl acetate.The organic layer is then washed with saturated aqueous sodium chlorideand dried over anhydrous magnesium sulfate. The solvent is removed underreduced pressure to provide the desired product as a yellow oil (0.20g).

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

1-(3-Methoxy-phenyl)-ethylamine

1-(4-Fluoro-phenyl)-propylamine

1-Naphthalen-2-yl-ethylamine

4-(1-Amino-ethyl)-benzonitrile

1-(4-Trifluoromethyl-phenyl)-ethylamine

1-(4-Methoxy-phenyl)-ethylamine

1-Prop-2-ynyl-pyrrolidine

1-(2-Methoxy-phenyl)-ethylamine

1-m-Tolyl-ethylamine

1-(2-Bromo-phenyl)-ethylamine

1-o-Tolyl-ethylamine

C-(4-Fluoro-phenyl)-C-phenyl-methylamine

1-(4-Fluoro-phenyl)-pentylamine

1-(4-Fluoro-phenyl)-2-phenyl-ethylamine

1-(2-Trifluoromethyl-phenyl)-ethylamine

1-(3-Bromo-phenyl)-ethylamine

1-(3-Chloro-phenyl)-ethylamine

[4-(1-Amino-ethyl)-phenyl]-dimethyl-amine

1-(1-Methyl-1H-pyrrol-2-yl)-ethylamine

1-Thiophen-3-yl-ethylamine

1-[3,5-bis(trifluoromethyl)phenyl]propylamine

1-[3,5-bis(trifluoromethyl)phenyl]-1-butanamine or1-[3,5-bis(trifluoromethyl)phenyl]butylamine

1-[3,5-bis(trifluoromethyl)phenyl]-1-pentanamine

1-(4-methylphenyl)ethanamine

1-[3-(trifluoromethyl)phenyl]ethylamine

1-[4-(trifluoromethyl)phenyl]ethylamine

1-(3-methylphenyl)ethanamine

1-(3,4-dichlorophenyl)ethanamine

1-(2-Bromo-phenyl)-ethylamine

1-(2-Trifluoromethyl-phenyl)-ethylamine

1-(3-Bromo-phenyl)-ethylamine

1-(3-Chloro-4-methoxy-phenyl)-ethylamine

4-(1-Amino-ethyl)-N,N-dimethyl-benzenesulfonamide

1-[4-(Piperidine-1-sulfonyl)-phenyl]-ethylamine

1-Quinolin-6-yl-ethylamine

1-(3,5-Bis-trifluoromethyl-phenyl)-ethylamine

4-[(1S)-1-aminoethyl]benzonitrile

(S)-alpha-Methyl-3,5-bis(trifluoromethyl)-benzenemethanamine(S)-alpha-Methyl-3,5-bis(trifluoromethyl)-benzenemethanamine

1-Biphenyl-4-yl-ethylamine

1-(4-Fluoro-phenyl)-ethylamine

1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanamine

1-[4-chloro-3-(trifluoromethyl)phenyl]ethanamine

N-{4-[(1R)-1-aminoethyl]phenyl}-1,2,3-thiadiazole-4-carboxamide

N-{4-[(1S)-1-aminoethyl]phenyl}-1,2,3-thiadiazole-4-carboxamide

1-[3-fluoro-5-(trifluoromethyl)phenyl]ethylamine

1-[2-fluoro-4-(trifluoromethyl)phenyl]ethylamine

1-[2-fluoro-5-(trifluoromethyl)phenyl]ethylamine

1-(2,4-dichlorophenyl)ethylamine

1-(2,4-dimethylphenyl)ethylamine

1-[2,4-bis(trifluoromethyl)phenyl]ethylamine

1-(2-chloro-4-fluorophenyl)ethylamine

1-(3,4-difluorophenyl)ethylamine

1-(4-bromo-2-fluorophenyl)ethylamine

1-(3-fluorophenyl)ethylamine

1-(2,4-difluorophenyl)ethylamine

1-[3-fluoro-4-(trifluoromethyl)phenyl]ethylamine

1-[4-fluoro-2-(trifluoromethyl)phenyl]ethylamine

1-(3-chloro-4-fluorophenyl)ethylamine

1-(4-chloro-3-fluorophenyl)ethylamine

1-(3,4-dibromophenyl)ethylamine

1-(2-bromo-4-fluorophenyl)ethanamine1-(2-bromo-4-fluorophenyl)ethylamine

EXAMPLE 73 METHOD 49 (2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile

A solution of 2-fluoro-5-trifluoromethylphenol (25 g) in reagent gradeacetone (0.55 L) is treated with solid potassium carbonate (7.7 g)followed by the rapid addition of neat bromoacetonitrile (10 mL). Theheterogenous mixture is stirred vigorously for approximately 20 hourswhereupon it is poured into water and extracted into diethyl ether. Thecombined ether extracts are washed with saturated sodium chloride anddried over anhydrous potassium carbonate. Filtration and concentrationunder reduced pressure gives a pale orange solid which is thenchromatographed on silica gel, eluting with dichloromethane, to give thedesired product as white solid (28.3 g).

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

(3-Bromo-phenylsulfanyl)-acetonitrile

(3-Chloro-phenylsulfanyl)-acetonitrile

(4-Iodo-phenoxy)-acetonitrile

(3-Trifluoromethyl-phenylsulfanyl)-acetonitrile

(3,5-Dichloro-phenylsulfanyl)-acetonitrile

(3,4-Dichloro-phenylsulfanyl)-acetonitrile

(3,4-Dichloro-phenoxy)-acetonitrile

(2-Fluoro-phenoxy)-acetonitrile

(3-Fluoro-phenoxy)-acetonitrile

(2-Chloro-phenoxy)-acetonitrile

(3-Bromo-phenoxy)-acetonitrile

(2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile

(3-Iodo-phenoxy)-acetonitrile

(4-Bromo-phenoxy)-acetonitrile

EXAMPLE 74 METHOD 50 3-Fluoro-5-trifluoromethylphenethylamine Tosylate

A solution of 2.5 g of 3-fluoro-5-trifluoromethylphenylacetonitrile and2.34 g (12.3 mmol) of p-toluenesulfonic acid in 75 ml of ethylene glycolmonomethyl ether is hydrogenated for 3 hours at room temperature at 40psi, using 200 mg 10% palladium on carbon catalyst. The catalyst isfiltered off and the solvent evaporated to half the volume. Uponstanding, the p-toluenesulfonic acid salt of the desired3-fluoro-5-trifluoromethylphenethylamine crystallizes. The whitecrystals, 4.26 g (91%) are collected by filtration.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

2-(3,5-Difluoro-phenyl)-ethylamine

2-(4-Trifluoromethyl-phenyl)-ethylamine

2-(3,4-Difluoro-phenyl)-ethylamine

2-(2-Fluoro-phenyl)-ethylamine

2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethylamine

2-(2-Fluoro-3-trifluoromethyl-phenyl)-ethylamine

2-(2,4-Bis-trifluoromethyl-phenyl)-ethylamine

2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethylamine

EXAMPLE 75 METHOD 51(4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine

A solution of 4-dimethylamino-3-trifluoromethylbenzonitrile (0.35 g) intetrahydrofuran (2 mL) is slowly added to a suspension of lithiumaluminum hydride (0.1 g) in tetrahydrofuran (2 mL) at 0° C. and stirredunder an atmosphere of argon for 2 hours. While at 0° C. water (0.1 mL)is slowly added followed by 5% sodium hydroxide (0.1 mL) and water (0.3mL). The resulting gray solid is filtered and washed withtetrahydrofuran. The filtrates are collected and concentrated underreduced pressure and the resulting oil is chromatographed over silicagel (15% methanol in methylene chloride is used as the eluant) toprovide the desired product as a pale orange oil (0.164 g).

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

4-Piperidin-1-yl-3-trifluoromethyl-benzylamine

(4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine

4-(4-Methyl-piperazin-1-yl)-3-trifluoromethyl-benzylamine

(3-Aminomethyl-5-trifluoromethyl-phenyl)-dimethyl-amine

[3-(2-Amino-ethyl)-5-trifluoromethyl-phenyl]-dimethyl-amine

[4-(2-Amino-ethyl)-2-methyl-phenyl]-dimethyl-amine

EXAMPLE 76 METHOD 52 3-Dimethylamino-5-trifluoromethyl-benzaldehyde

Diisobutylaluminum hydride (10 mL of a 1M solution in methylenechloride) is added dropwise to a solution of3-dimethylamino-5-trifluoromethylbenzonitrile (1.06 g) in methylenechloride (25 mL) at 0° C. and the mixture stirred for 2 hours. Whilestill at 0° C. a saturated aqueous solution of sodium potassium tartrate(8 mL) is slowly added and the solution is stirred for 1.5 hours. Thereaction mixture is then extracted with ethyl acetate, dried overanhydrous magnesium sulfate and concentrated under reduced pressure toprovide the desired product as a yellow solid (0.97 g).

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

3-Dimethylamino-5-trifluoromethyl-benzaldehyde

4-Dimethylamino-3-methyl-benzaldehyde

EXAMPLE 77 METHOD 53Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine

Nitromethane (0.473 g) is added to a solution of3-dimethylamino-5-trifluoromethyl-benzaldehyde (0.885 g) and ammoniumacetate (0.339 g) in acetic acid (3.4 mL) and the solution is heated at110° C. for 6 hours. The reaction mixture is cooled to 0° C. and a solidforms which is filtered and washed with 1:1 water-acetic acid. Thissolid is recrystallized from ethanol to provide the desired product as ared solid (0.39 g).

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine

Dimethyl-[2-methyl-4-(2-nitro-vinyl)-phenyl]-amine

EXAMPLE 78 METHOD 54 3-(4-Bromo-phenyl)-propionitrile

Diethylazodicarboxylate (5.2 g) is added dropwise to a solution of4-bromo-phenethylalcohol (2.01 g), and triphenylphosphine (7.9 g) indiethyl ether (16 mL) at 0° C. The reaction mixture is stirred for 10minutes and a solution of acetone cyanohydrin (2.6 g) in diethyl ether(10 mL) is added. The clear orange solution is stirred for 5 minutes at0° C. and then at 25° C. for 12 hours. The reaction mixture is thenfiltered, and washed with diethyl ether. The filtrate is concentratedunder reduced pressure and chromatographed over silica gel (10% ethylacetate-hexanes is used as the eluant) to provide the desired product asa pale yellow oil (2.04 g).

EXAMPLE 79 METHOD 55 3-Dimethylamino-2-isocyano-acrylic Acid Ethyl Ester

To a solution of ethyl isocyanoacetate (5.0 g) in ethanol (100 mL) isadded N,N-dimethyl-formamide dimethyl acetal (6.5 g) dropwise withstirring over 10 minutes. The reaction is stirred for 24 hours and theethanol is evaporated. The resulting oil is passed through magnesiumsilicate using 50% ethyl acetate-hexanes as the eluant. The solvents areremoved and the resulting oil is crystallized from ethyl acetate-hexanesto yield light yellow needles, 3.0 g.

EXAMPLE 80 METHOD 56 4-Carboethoxythiazole

A solution of 3-dimethylamino-2-isocyano-acrylic acid ethyl ester (1.0g) and triethylamine (3.0 g) in tetrahydrofuran (30 mL) is treated withgaseous hydrogen sulfide until all starting material is consumed. Themixture is concentrated to an oil and purified by column chromatographyusing silica and 25% ethyl acetate-hexanes as the eluant. The purifiedmaterial (0.61 g) is isolated as an oil.

EXAMPLE 81 METHOD 34N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-fluoro-benzamide

A suspension of N-(4-amino-phenyl)-2-fluoro-benzamide (0.43 g) inacetonitrile (4 mL) is treated with5-chloro-2,4-dimethoxyphenylisocyanate (0.40 g). The mixture becomes asolution and is allowed to stand for 12 hours. A white solid forms andis collected by filtration (0.79 g). [M+H] 444.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

EX NO. M + H COMPOUND NAME 81 445N-∴5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-uriedo]-phenyl}-2-fluoro-benzamide82 441N-∴5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-uriedo]-phenyl}-2-methyl-benzamide83 435 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-ureido]- phenyl}-amide 84 443[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)- ureido]-phenyl}-amide 85 453N-∴5-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl}-2-fluoro-benzamide86 409 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-ureido[-phenyl}- amide 87 486N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-ureido]-phenyl}-2-fluoro-benzamide88 458 Furan-2-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-ureido]-phenyl}-amide 89 476[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-{3,5-bis-trifluoromethyl-phenyl)-ureido]- phenyl}-amide 90 423[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-dichloro-benzyl)-ureido]-phenyl}- amide

EXAMPLE 91 METHOD 31N-(5-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2-pyrdinyl)-1,3-thiazole-4-carboxamide

A mixture of N-(5-isothiocyanato-2-pyridinyl)-1,3-thiazole-4-carboxamide(0.36 g) and(S)-alpha-methyl-3,5-bis(trifluoromethyl)-benzenemethanamine (0.36 g) isheated with acetonitrile (10 mL) until all solids are dissolved. Thesolution is allowed to stand for 12 hours. A white solid forms and iscollected by filtration (0.40 g). [M+H] 520.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

EX. NO. M + H COMPOUND NAME 92 506[3-Chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)phenyl]-carbamic acid tert-butyl ester 93 4091-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-morpholin-4-yl-phenyl)-thiourea94 3701-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-methylsulfanyl-phenyl)-thiourea95 338 1-(5-Chloro-2,4-dimethoxy-phenyl)-3-p-tolyl-thiourea 96 414{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylsulfanyl}-aceticacid 97 3841-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(2-hydroxy-ethoxy)-phenyl]-thiourea 98 395N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-hydroxy-phenyl)-thiourea 99395N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-N-methyl-acetamide 100 381N-{3-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide101 411{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidethyl ester 102 3191-(2,4-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-thiourea 103 346N-{4-[3-(2,4-Dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 104 316N-{4-[3-(4-Methoxy-phenyl)-thioureido]-phenyl}-acetamide 105 316N-{4-[3-(2-Methoxy-phenyl)-thioureido]-phenyl}-acetamide 106 351N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 107351 N-{4-[3-(5-Chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide108 371N-{4-[3-(3,5-Dichloro-4-hydroxy-phenyl)-thioureido]-phenyl}-acetamide109 385N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide110 381N-{4-[3-(4-Chloro-2,5-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide111 389 N{4-[3-(2-Chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide 112 389N{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide 113 422 Benzoic acid4-[3-(4-acetylamino-phenyl)-thioureido]-3-hydroxy- phenylester 114 457N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methyl-benzamide 115 501 Acetic acid2-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl-carbamoyl}-phenyl ester 116 461N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-fluoro-benzamide 117 461N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide 118 461N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 119 473N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methoxy-benzamide 120 473N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide 121 473N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide 122 443N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide123 417N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-methane-sulfonamide 124 331N-{4-[3-(3-Nitro-phenyl)-thioureido]-phenyl}-acetamide 125 3391-(3-Chloro-4-methoxy-phenyl)-3-(3-nitro-phenyl)-thiourea 126 337N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl}-acetamide 127439 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamicacid tert-butyl ester 128 351N-{4-[3-(3-Chloro-4-hydroxy-5-methyl-phenyl)-thioureido]-phenyl}-acetamide 129 385N-{4-[3-(3,5-Dichloro-4-hydroxy-2-methyl-phenyl)-thioureido]-phenyl}-acetamide 130 318N-{4-[3-(2,4-Dihydroxy-phenyl)-thioureido]-phenyl}-acetamide 131 414N0{4-[3-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide 132 332N-{4-[3-(2-Hydroxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 133465N0{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-fluoro-benzamide 134 5003-Acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 135 488N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-nitro-benzamide- 136 486N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-dimethylamino-benzamide 137 536N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-methane-sulfony-amino-benzamide 138 511N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-trifluoro-methyl-benzamide 139 459N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-hydroxy-benzamide 140 479N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 141 4772-Chloro-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 142 5222-Bromo-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 143 488N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-nitro-benzamide 144 445 Pyrazine-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 145 4635-Methyl-thiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 146 494 Quinoline-8-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 147 4461-Methyl-1H-pyrrole-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 148 3691-(5-Chloro-2,4-dimethoxy-phenyl)-3-(2-nitro-phenyl)-thiourea 149 3691-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-nitro-phenyl)-thiourea 150 425N{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 151376 N{4-[3-(3,4,5-Trimethoxy-phenyl)-thioureido]-phenyl}-acetamide 152399N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 153 499 Benzo[b]thiophene-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-phenyl}-amide 154 483Benzofuran-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 155 444N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-isonicotinamide 156 493 Naphthalene-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 157 493Naphthalene-1-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 158 494 Isoquinoline-1-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 159 494Quinoline-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 160 444N0{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-nicotinamide 161 478 5-Nitro-furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amidecarbamicacid phenyl ester 162 459{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- 163 4675-Chloro-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 164 439{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidisobutyl ester 165 397{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidmethyl ester 166 433 Furan-3-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 167 4473-Methyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 168 512 5-Bromo-furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 169 5124-Bromo-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 170 433 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 171 467{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidhexyl ester 172 491 Isoquinoline-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 173 451[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 174 4341H-[1,2,3]Triazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 175 528 3-Bromo-thiophene-2-carboxylicacid {4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-phenyl}-amide176 399N-{4-[3-(3,5-Dichloro-4-ethoxy-phenyl)-thioureido]-phenyl}-acetamide 177427 N-{4-[3-(4-Butoxy-3,5-dichloro-phenyl)-thioureido]-phenyl}-acetamide178 461 N-{4-[3-(4-Benzyloxy-3,5-dichloro-phenyl)-thioureido]-phenyl}-acetamide 179 381N-{4-[3-(3-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide180 530(3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}-phenyl)-carbamic acid ethyl ester 181 4582-Amino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 182 519 Biphenyl-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 183 4691-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-phenyl]-thiourea 184 487N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- phthalamicacid 185 473N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-hydroxy-methyl-benzamide 186 479N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3-difluoro-benzamide 187 479N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,5-difluoro-benzamide 188 479N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,4-difluoro-benzamide 189 5002-Acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 190 4411-(5-Chloro-2,4-dimethoxy-phenyl)-3-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-thiourea 191 536N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2methane-sulfonylamino-benzamide 192 497N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3,4-trifluoro-benzamide 193 533N-{4-[3-(5-cloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3,4,5,6-pentafluoro-benzamide 194 489N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methyl-sulfanyl-benzamide 195 431 5-Methyl-furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy- phenyl)-ureido]-phenyl}-amide 196 4675-Difluoromethyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-amide 197 472N-{4-[3-(5-Iodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 198364N-{4-[3-(5-Fluoro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide199 365N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 200 459 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl- phenyl)-thioureido]-phenyl}-amide 201455 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-amide 202 392N-{4-[3-(3-Chloro-4-diethylamino-phenyl)-thioureido]-phenyl}-acetamide203 432N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-acetamide 204 506 1-Hydroxy-naphthalene-2-carboxylic acid{4-[3-(4-acetylamino-phenyl)- thioureido]-2-chloro-phenyl}-amide 205 406N-{4-[3-(3-Chloro-4-morpholin-4-yl-phenyl)-thioureido]-phenyl}-acetamide 206 4431-(5-Chloro-2,4-dimethoxy-phenyl)-3-(3-chloro-4-morpholin-4-yl-phenyl)-thiourea 207 3721-(5-Chloro-2,4-dimethoxy-phenyl)-3-(5-chloro-2-methyl-phenyl)-thiourea208 501 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-isophthalamic acid methyl ester 209 487N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-isophthalamic acid 210 5493-Benzyloxy-N-{8-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 211 434N-(4-{3-[5-Chloro-2-methoxy-4-(4-nitrilo-butoxy)-phenyl]-thioureido}-phenyl)-acetamide 212 406N-(4-{3-[5-Chloro-2-methoxy-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide 213 406N-(4-{3-[5-Chloro-4-methoxy-2-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide 214 411N-(4-{3-[5-Chloro-2-(2-hydroxy-ethoxy)-4-methoxy-phenyl]-thioureido}-phenyl)-acetamide 215 411N-(4-{3-[5-Chloro-4-(2-hydroxy-ethoxy)-2-methoxy-phenyl]-thioureido}-phenyl)-acetamide 216 481{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-acetic acid tert-butyl ester 217 439{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-acetic acid methyl ester 218 481{2-[3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-phenoxy}-acetic acid tert-butyl ester 219 5153-Butoxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-benzamide 220 505N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methane-sulfinyl-benzamide 221 545(3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}-phenoxy)-acetic acid ethyl ester 222 517(3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}-phenoxy)-acetic acid 223 367N-{4-[3-(5-Chloro-4-hydroxy-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide 224 444 Pyridine-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 225 494Quinoline-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 226 436N-{4-[3-(5-Chloro-4-methoxy-2-morpholin-4-yl-phenyl)-thioureido]-phenyl}-acetamide 227 394N-{4-[3-(5-Chloro-2-dimethylamino-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 228 420N-{4-[3-(5-Chloro-4-methoxy-2-pyrrolidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide 229 434N-{4-[3-(5-Chloro-4-methoxy-2-piperidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide 230 405 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-methyl-phenyl)- thioureido]-phenyl}-amide 231 415N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 232 427N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide 233 387 Furan-2-carboxylic acid{4-[3-(3-chloro-4-methyl-phenyl)-thioureido]- phenyl}-amide 234 411N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-methyl-benzamide 235 433N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 236 398 Pyridine-2-carboxylic acid{4-[3-(3-chloor-4-methyl-phenyl)-thioureido]- phenyl}-amide 237 502[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido]-phenyl)-amide 238 512N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 239 404N-{4-[3-(3-Chloro-4-piperidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide240 364 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-acetamide 241 426N-{4-[3-(4-Benzylamino-3-chloro-phenyl)-thioureido]-phenyl}-acetamide242 390 N-{4-[3-(3-Chloro-4-pyrrolidin-1-yl-phenyl)-thioureido]-phenyl}-acetamide 243 419N-(4-{3-[3-Chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-thioureido}-phenyl)-acetamide 244 469N-{-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 245 422N-{4-[3-(2-Benzylamino-4-methoxy-phenyl)-thioureido]-phenyl}- acetamide246 484 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-amide 247 508N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-2-methyl-benzamide 248 530N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-2,6-difluoro-benzamide 249 495 Pyridine-2-carboxylic acid(4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-amide 250 524N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-3-methoxy-benzamide 251 376N-(4-{3-[3-Chloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide 252 393N-{4-[3-(4-sec-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 253501 Acetic acid3-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl-carbamoyl}-phenyl ester 254 459N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-hydroxy-benzamide 255 487 Benzo[1,3]dioxole-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-phenyl}-amide 256 527N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-trifluoro-methoxy-benzamide 257 530N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-(2-dimethylamino-ethoxy)-benzamide 258 572N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-(2-morpholin-4-yl-ethoxy)-benzamide 259 406N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl}-acetamide 260 521N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy-phenyl}-2-fluoro-benzamide 261 441N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy-phenyl}-acetamide 262 5272-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenoxy}-5-chloro-benzenesulfonic acid 263 5622-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenoxy}-4,5-dichloro-benzenesulfonic acid 264 5274-Phenyl-[1,2,3]thiadiazole-5-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 265 381N-(4-{3-[3-Chloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido]-phenyl)-acetamide 266 393 N-{4-[3-(4-Butoxy-3-chloro-phenyl}-acetamide 267 446N-(4-{3-[3-Chloro-4-(cyclohexyl-ethyl-amino)-phenyl]-thioureido}-phenyl)-acetamide 268 365N-{4-[3-(3-Chloro-4-ethoxy-phenyl)-thioureido]-phenyl}-acetamide 269 427N-{4-[3-(4-Benzyloxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 270317 {4-[(3-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamicacidtert-butyl ester 271 456N-{4-[3-(2-Benzylamino-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 272 420N-{4-[3-(3-Chloro-4-dipropylamino-phenyl)-thioureido]-phenyl}- acetamide273 458N-(4-{3-[4-(Allyl-cyclohexyl-amino)-3-chloro-phenyl]-thioureido}-phenyl)-acetamide 274 411N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl}-acetamide 275 415N-{2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 276 493 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy-phenyl}-amide 277 486N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl}-2-fluoro-benzamide 278 495N-{2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 279 465 5-Methyl-[1,2,3]thidaizole-4-carboxylicacid{4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}-amide 280517 5-Furan-3-yl-[1,2,3]thiadiazole-4-carboxylicacid{4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl}amide 281527 5-Phenyl-[1,2,3]thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}amide 282 458N-(4-{3-[3-Chloro-4-(octahydro-quinolin-1-yl)-phenyl]-thioureido}-phenyl)-acetamide 283 458N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-pyridinyl]-2-methylbenzamide 284 434 Furan-2-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-2-yl}-amide285 425 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl-phenyl}-acetamide 286 505N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl-phenyl}-2-fluoro-benzamide 287 477 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl-phenyl}-amide 288 5174-Furan-3-yl-[1,2,3]thiadiazole-5-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 289 462N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-2-fluoro-benzamide 290 384N-{4-[3-(4-Methoxy-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide 291 394N-[4-(3-{3-Chloro-4-[(2-hydroxy-ethyl)-methyl-amino]-phenyl}-thioureido)-phenyl]-acetamide 292 485N-{2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide 293 565N-{2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 294 537 Furan-2-carboxylic acid{2-benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 295 475N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-2-fluoro-benzamide 296 447 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-amide 297 395N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-acetamide 298 435N-[4-(3-{3-Chloro-4-[(3-dimethylamino-propyl)-methyl-amino]-phenyl}-thioureido)-phenyl]-acetamide 299 418N-{4-[3-(3-Chloro-4-cyclohexylamino-phenyl)-thioureido]-phenyl}-acetamide 300 421N-[4-(3-{3-Chloro-4-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-thioureido)-phenyl]-acetamide 301 5805-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-[(2-fluorobenzoyl)amino]-N-phenyl-benzamide 302 552 Furan-2-carboxylicacid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-phenylcarbamoyl-phenyl}-amide 303 491N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl}-2-fluoro-benzamide 304 463 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl}-amide 305 449N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl}-acetamide 306 458 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-2-cyano-phenyl}-amide307 467 Furan-2-carboxylic acid {2-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 308 501 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl}-amide 309 395N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-acetamide 310 475N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}2-fluoro-benzamide 311 447 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-amide 312 378N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}- acetamide313 408 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-carbamic acid ethyl ester 314 382N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-acetamide 315 509N-(4-{3-[4-(1-Benzyl-piperidin-4-ylamino)-3-chloro-phenyl]-thioureido}-phenyl)-acetamide 316 407N-(4-{3-[3-Chloro-4-(2-dimethylamino-ethylamino)-phenyl]-thioureido}-phenyl)-acetamide 317 408N-[4-(3-{3-Chloro-4-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-thioureido)-phenyl]-acetamide 318 421N-(4-{3-[3-Chloro-4-(3-dimethylamino-propylamino)-phenyl]-thioureido}-phenyl)-acetamide 319 495N-(4-{3-[4-(1-Benzyl-pyrrolidin-3-ylamino)-3-chloro-phenyl]-thioureido}-phenyl)-acetamide 320 483 Furan-2-carboxylic acid{5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-hydroxy-phenyl)-amide 321 431N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-hydroxy-phenyl}-acetamide 322 511(5H,11H-Benzo[e]pyrrolo[1,2-a][1,4]diazepin-10-yl)-(2-chloro-4-imidazol-1-yl-phenyl)-methanone 323 451 [1,2,3]Thiadiazole-5-carboxylicacid {4-[3-(5-chloro-2,4-dimeth- oxy-phenyl)-thioureido]-phenyl}-amide324 483 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl}-amide 325 511N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl}-2-fluoro-benzamide 326 429N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-acetamide 327 509N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide 328 481 Furan-2-carboxylic acid{5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}-amide 329 431N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-1-yl}-acetamide 330 416 Furan-2-carboxylic acid{4-[3-(3-chloro-4-dimethylamino-phenyl)- thioureido]-phenyl}-amide 331561 Furan-2-carboxylic acid [4-(3-{4-[(1-benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-amide 332 513N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 333 463N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2,5-difluoro-benzamide 334 420N-(4-{3-[3-Chloro-4-(1-methyl-pyrrolidin-3-yloxy)-phenyl]-thioureido}-phenyl)-acetamide 335 434N-(4-{3-[3-Chloro-4-(1-methyl-piperidin-4-yloxy)-phenyl]-thioureido}-phenyl)-acetamide 336 422N-(4-{3-[3-Chloro-4-(3-dimethylamino-propoxy)-phenyl]-thioureido}-phenyl)-acetamide 337 4252-Acetylamino-5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- benzoicacid 338 5055-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-(2-fluoro-benzoylamino)-benzoic acid 339 4775-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-[(furan-2-carbonyl)-amino]-benzoic acid 340 545N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-2,6-difluoro-benzamide 341 503[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-amide 342 443N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-methyl-benzamide 343 408N-(4-{3-[3-Chloro-4-(2-methylamino-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide 344 499 Furan-2-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-amide 345 419N-{4-[3-(3-Chloro-4-cyclohexyloxy-phenyl)-thioureido]-phenyl}- acetamide346 440 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2-methyl-benzamide 347 493N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-2,6-difluoro-benzamide 348 462N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 349 531N-[4-(3-{3-Chloro-4-[kethyl-(1-methyl-pyrrolidin3-yl)-amino]-phenyl}-thioureido)-phenyl]-2,6-difluoro-benzamide 350 427 Pyridine-2-carboxylicacid {4-[3-(3-chloro-4-dimethylamino-phenyl)- thioureido]-phenyl}-amide351 430 Pyridine-2-carboxylic acid{4-[3-(3-chloro-4-methylsulfanyl-phenyl)- thioureido]-phenyl}-amide 352428 Pyridine-2-carboxylic acid{4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)- thioureido]-phenyl}-amide353 417 Furan-2-carboxylic acid{4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)- thioureido]-phenyl}-amide354 496 Pyridine-2-carboxylic acid [4-(3-{3-chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-amide 355 495N-{3-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 356 467 Furan-2-carboxylic acid{3-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-amide 357 515N-{4-[3-(3-Chloro-4-cyclohexylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 358 449N0{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-phenyl}-acetamide 359 529N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl-phenyl}-2-fluoro-benzamide 360 421N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-dimethyl-amino-acetamide 361 473 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-dimethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-amide 362 501N-(4-{3-[3-Chloro-4-(2-dimethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 363 461N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-piperidin-1-yl-acetamide 364 541N-(4-{3-[3-Chloro-4-(2-piperidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 365 513 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-piperidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide 366 463N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-morpholin-4-yl-acetamide 367 543N-(4-{3-[3-Chloro-4-(2-morpholin-4-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 368 515 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-morpholin-4-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide 369 414N-{4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl}-acetamide 370 494N-{4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 371 466 Furan-2-carboxylic acid{4-[3-(3-chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl}-amide 372 481N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-(2-dimethy-lamino-ethylsulfanyl)-acetamide 373 561N-[4-(3-{3-Chloro-4-[2-(2-dimethylamino-ethylsulfanyl)-acetylamino]-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 374 585N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-2-methyl-benzamide 375 523N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-2-methyl-benzamide 376 510 Pyridine-2-carboxylicacid [4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-amide 377 347N-{4-[3-(3-Chloro-4-vinyl-phenyl)-thioureido]-phenyl}-acetamide 378 441Furan-2-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 379 452 Pyridine-2-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide 380487 N0{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 381 486N-{4-[3-(5-Chloro2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl}-2-fluoro-benzamide 382 458 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-3-cyano-phenyl}-amide383 406N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl}-acetamide 384 395N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-2-methyl-isothioureido]-phenyl}-acetamide 385 396N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-2-methyl-isothioureido]-phenyl}-acetamide 386 461N-{4-[3-(3-Chloro-4-ethylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 387 489N-{4-[3-(4-Butylsulfanyl-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 388 411N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-acetamide 389 491N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide 390 463 Furan-2-carboxylic acid{4[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-amide 391 531[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(2-piperidin-1-yl-acetyl-amino)-phenyl]-thioureido}-phenyl)-amide 392 481N-{4-[3-(3-Chloro-4-methanesulfinyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 393 497N-{4-[3-(3-Chloro-4-methanesulfonyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 394 459N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide 395 429N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide 396 533 Furan-2-carboxylic acid[4-(3-{3-chloro-4-[2-(2-dimethylamino-ethylsulfanyl)-acetylamino]-phenyl}-thioureido)-phenyl]-amide 397 458N-{4-[3-(4-Acetylamino-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 398 460[2-Chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-carbamic acid ethyl ester 399 488(2-Chloro-4-{3-[4-(2-fluoro-benzoylamino)-phenyl]-thioureido}-phenyl)-carbamic acid ethyl ester 400 440N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-benzamide401 520 N-{40[({[4-(Benzoylamino)-3-chloro-phenyl]-amino}-thioxomethyl)-amino]-phenyl}-2-fluoro-benzamide 402 529N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl-phenyl}-2-fluoro-benzamide 403 492 Furan-2-carboxylic acid{4-[3-(4-benzoylamino-3-chloro-phenyl)- thioureido]-phenyl}-amide 404416 N-{4-[3-(4-Amino-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 405 479N0{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-thiomorpholin-4-yl-acetamide 406 531 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-thiomorpholin-4-yl-acetyl-amino)-phenyl]-thioureido}-phenyl)-amide 407 559N-(4-{3-[3-Chloro-4-(2-thiomorpholin-4-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 408 461N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide 409 430 Furan-2-carboxylic acid{4-[3-(4-acetylamino-3-chloro-phenyl)- thioureido]-phenyl}-amide 410 477N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-dipropyl-amino-acetamide 411 529 Furan-2-carboxylic acid(4-{3[3-chloro-4-(2-dipropylamino-acetylamino)-phenyl]-thioureido}-phenyl)-amide 412 449N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-diethyl-amino-acetamide 413 501 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-diethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-amide 414 529N-(4-{3-[3-Chloro-4-(2-diethylamino-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 415 447N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-pyrrolidin-1-yl-acetamide 416 499 Furan-2-carboxylic acid(4-{3-[3-chloro-4-(2-pyrrolidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-amide 417 527N-(4-{3-[3-Chloro-4-(2-pyrrolidin-1-yl-acetylamino)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 418 475N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide 419 445N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide 420 477N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-3-methoxy-phenyl}-2-fluoro-benzamide 421 388 Furan-2-carboxylic acid{4-[3-(4-amino-3-chloro-phenyl)-thioureido]- phenyl}-amide 422 527Furan-2-carboxylic acid (4-{3-[4-(2-azepan-1-yl-acetylamino)-3-chloro-phenyl]-thioureido}-phenyl)-amide 423 555N-(4-{3-[4-(2-Azepan-1-yl-acetylamino)-3-chloro-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 424 527 Furan-2-carboxylic acid[4-(3-{3-chloro-4-[2-(2-methyl-piperidin-1-yl)-acetyl-amino]-phenyl}-thioureido)-phenyl]-amide 425 555N-[4-(3-{3-Chloro4-[2-(2-methyl-piperidin-1-yl)-acetylamino -phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 426 339 Furan-2-carboxylic acid[4-(3-pyridin-2-yl-thioureido)-phenyl]-amide 427 339 Furan-2-carboxylicacid [4-(3-pyridin-4-yl-thioureido)-phenyl]-amide 428 3672-Fluoro-N-[4-(3-pyridin-3-yl-thioureido)-phenyl]-benzamide 429 339Furan-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)-phenyl]-amide 430353 Furan-2-carboxylic acid {4-[3-(3-amino-phenyl)-thioureido]-phenyl}-amide 431 406 Furan-2-carboxylic acid{4-[3-(3-trifluoromethyl-phenyl)-thioureido]- phenyl}-amide 432 3802-Fluoro-N-[4-(3-m-tolyl-thioureido)-phenyl]-benzamide 433 4342-Fluoro-N-{4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 434 381N-{4-[3-(3-Amino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 435 388Furan-2-carboxylic acid {4-[3-(3-amino-5-chloro-phenyl)-thioureido]-phenyl}-amide 436 352 Furan-2-carboxylic acid{4-(3-m-tolyl-thioureido)-phenyl]amide 437 416N-{4-[3-(2-Amino-5-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 438 571(2-Chloro-4-{3-[4-(2-fluoro-benzoylamino)-phenyl]-thioureido}-phenyl)-carbamic acid 2-piperidin-1-yl-ethyl ester 439 543[2-Chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-carbamic acid 2-piperidin-1-yl-ethyl ester 440 388Furan-2-carboxylic acid {4-[3-(2-amino-5-chloro-phenyl)-thioureido]-phenyl}-amide 441 363 Furan-2-carboxylic acid{4-[3-(3-cyano-phenyl)-thioureido]-phenyl}- amide 442 416N-{4-[3-(3-Amino-5-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 443 3672-Fluoro-N-[4-(3-pyridin-2-yl-thioureido)-phenyl]-benzamide 444 3672-Fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]-benzamide 445 374Furan-2-carboxylic acid{4-[3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl}- amide 446 388Furan-2-carboxylic acid {4-[3-(2-amino-3-chloro-phenyl)-thioureido]-phenyl)-amide 447 396 Furan-2-carboxylic acid{4-[3-(3-hydrazinocarbonyl-phenyl)-thioureido]- phenyl}-amide 448 4102-Fluoro-N-(4-{3-[3-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-benzamide 449 414 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-hydrazinocarbonyl-phenyl)- thioureido]-phenyl}-amide 450 399[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl}-amide 451 380 Furan-2-carboxylic acid{4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl}- amide 452 4092-Fluoro-N-{4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl}-benzamide 453381 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-cyano-phenyl)-thioureido]- phenyl}-amide 454 410N-{4-[3-(3-Dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide455 381 Furan-2-carboxylic acid{4-[3-(3-dimethylamino-phenyl)-thioureido]- phenyl}-amide 456 370[1,2,3]Thiadiazole-4-carboxylic acid [4-(3-m-tolyl-thioureido)-phenyl]-amide 457 424 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide 458 479N-{3-Chloro-4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 459 449N-{3-Chloro-4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 460 481N-{3-Chloro-4-[3-(3-chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 461 391N-{4-[3-(3-Cyano-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 462 395Furan-2-carboxylic acid {4-[3-(3-acetylamino-phenyl)-thioureido]-phenyl}-amide 463 4242-Fluoro-N-{4-[3-(3-hydrazinocarbonyl-phenyl)-thioureido]-phenyl}-benzamide 464 400 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(1-hydroxy-ethyl)-phenyl]- thioureido}-phenyl)-amide 465 434N-{4-[3-(2-Amino-3-chloro-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 466 406 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-amino-5-chloro-phenyl)- thioureido]-phenyl}-amide 467 398Furan-2-carboxylic acid {4-[3-(3,5-dimethoxy-phenyl)-thioureido]-phenyl}-amide 468 416 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dimethoxy-phenyl)- thioureido]-phenyl}-amide 469 4545-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-isophthalic aciddimethyl ester 470 434 isoxazole-5-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 471 392[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl}-amide 472 382 Furan-2-carboxylic acid(4-{3-[3-(1-hydroxy-ethyl)-phenyl]-thioureido}- phenyl)-amide 473 368Furan-2-carboxylic acid {4-[3-(3-methoxy-phenyl)-thioureido]-phenyl}-amide 474 354 Furan-2-carboxylic acid{4-[3-(3-hydroxy-phenyl)-thioureido]-phenyl}- amide 475 3822-Fluoro-N-{4-[3-(3-hydroxy-phenyl)-thioureido]-phenyl}-benzamide 476396 2-Fluoro-N-{4-[3-(3-hydroxymethyl-phenyl)-thioureido]-phenyl}-benzamide 477 423N-{4-[3-(3-Acetylamino-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide478 413 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-acetylamino-phenyl)- thioureido]-phenyl}-amide 479 400[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-phenyl)-thioureido]-phenyl}-amide 480 340 Furan-2-carboxylic acid[4-(3-pyrimidin-4-yl-thioureido)-phenyl]-amide 481 378Furan-2-carboxylic acid {4-[3-(1H-indazol-5-yl)-thioureido]-phenyl}-amide 482 395 Furan-2-carboxylic acid[4-(3-benzothiazol-5-yl-thioureido)-phenyl]-amide 483 4062-Fluoro-N-{4-[3-(1H-indazol-5-yl)-thioureido]-phenyl}-benzamide 484 424N-[4-(3-Benzothiazol-5-yl-thioureido)-phenyl]-2-fluoro-benzamide 485 4735-(3-{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-isophthalic acid dimethyl ester 486 442 Furan-2-carboxylic acid(4-{3-[4-(1-azido-ethyl)-3-chloro-phenyl]- thioureido}-phenyl)-amide 487396 2-Fluoro-N-{4-[3-(3-methoxy-phenyl)-thioureido]-phenyl}-benzamide488 368 Furan-2-carboxylic acid{4-[3-(3-hydroxymethyl-phenyl)-thioureido]- phenyl}-amide 489 416Furan-2-carboxylic acid {4-[3-(5-chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-amide 490 444N-{4-[3-(5-Chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 491 506[3-Chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl]-thioureido)-phenyl]-carbamic acid tert-butyl ester 492 470N-(4-{3-[4-(1-Azido-ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 493 337 Furan-2-carboxylic acid[4-(1H-thiazolo[5,4-b]pyridin-2-ylideneamino)- phenyl]-amide 494 378Furan-2-carboxylic acid {4-[3-(1H-benzoimidazol-5-yl)-thioureido]-phenyl}-amide 495 392 Furan-2-carboxylic acid{4-[3-(2-methyl-1H-benzoimidazol-5-yl)- thioureido]-phenyl}-amide 496406N-{4-[3-(1H-Benzoimidazol-5-yl)-thioureido]-phenyl}-2-fluoro-benzamide497 4202-Fluoro-N-{4-[3-(2-methyl-1H-benzoimidazol-5-yl)-thioureido]-phenyl}-benzamide 498 452 [1,2,3]Thiadiazole-4-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-pyridin-2-yl}-amide499 445 Pyridine-2-carboxylic acid{5-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-2-yl}-amide500 434 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2-dimethylamino- phenyl)-thioureido]-phenyl}-amide 501484 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[4-(2-amino-pyrimidin-4-yl)-3-chloro-phenyl]-thioureido}-phenyl)-amide 502 494N-(4-{3-[4-(2-Amino-pyrimidin-4-yl)-3-chloro-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 503 434 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-2-dimethylamino- phenyl)-thioureido]-phenyl}-amide 504462 N-{4-[3-(3-Chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 505 416 Furan-2-carboxylic acid{4-[3-(3-chloro-2-dimethylamino-phenyl)- thioureido]-phenyl}-amide 506445 Pyridine-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide 507 462N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyhl)-thioureido]-pyridin-3-yl}-2-fluoro-benzamide 508 482 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-iodo-phenyl)-thioureido]- phenyl}-amide 509 413[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-tert-butyl-phenyl)-thioureido]-phenyl}-amide 510 387 Furan-2-carboxylic acid{4-[3-(3-chloro-benzyl)-thioureido -phenyl}- amide 511 415N-{4-[3-(3-Chloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 512 434Furan-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide 513 435 [1,2,3]Thiadiazole-4-carboxylicacid {4-[3-(3-bromo-phenyl)-thioureido]- phenyl}-amide 514 452[1,2,3]Thiadiazole-4-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-amide 515 426[1,2,3]Thiadiazole-4-carboxylic acid {5-[3-(3,5-dichloro-phenyl)-thioureido]-pyridin-2-yl}-amide 516 474 Furan-2-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide 517502 N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-Fluoro-Benzamide 518 450N-{4-[3-(4-Amino-3,5-dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 519 539N-{4-[3-(4-Amino-3,5-dibromo-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 520 392 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(5-chloro-pyridin-3-yl)- thioureido]-phenyl}-amide 521 529[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-amino-3,5-dibromo-phenyl)-thioureido]-phenyl}-amide 522 434[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-5-dimethylamino-phenyl)-thioureido]-phenyl}-amide 523 444N-{4-[3-(3-Chloro-5-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 524 416 Furan-2-carboxylic acid{4-[3-(3-chloro-5-dimethylamino-phenyl)- thioureido]-phenyl}-amide 525436 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-bromo-pyridin-3-yl)-thioureido]-phenyl}-amide 526 379 Furan-2-carboxylic acid{4-[3-(1H-benzotriazol-5-yl)-thioureido]-phenyl}- amide 527 425N-{4-[3-(1H-Benzotriazol-5-yl)-thioureido]-phenyl}-2,6-difluoro-benzamide 528 388N-[4-({[2-(3-Chloro-phenyl)-hydrazino]-thioxomethyl}-amino)-phenyl]-furan-2-carboxamide 529 416N-[4-({[2-(3-Chloro-phenyl)-hydrazino]-thioxomethyl}-amino)-phenyl]-2-fluoro-benzamide 530 456 Furan-2-carboxylic acid{4-[3-(2-amino-3-chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 531 513N-{4-[3-(3-Bromo-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 532 503 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-bromo-5-trifluorometyl- phenyl)-thioureido]-phenyl}-amide 533374 {4-[(Furan-2-carbonyl)-amino]-phenyl}-thiocarbamic acid O-(3-chloro-phenyl)ester 534 474 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-amino-3-chloro-5-trifluoro-methyl-phenyl)-thioureido]-phenyl}-amide 535 508[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-piperidin-1-yl-5-trifluoro-methyl-phenyl)-thioureido]-phenyl}-amide 536 380N-[4-(3-Benzyl-thioureido)-phenyl]-2-fluoro-benzamide 537 439[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}-amide 538 449N-{4-[3-(3,4-Dichloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 539370 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-benzyl-thioureido)-phenyl]- amide 540 424N-[4-(3-Benzo[1,3]dioxol-5-ylmethyl-thioureido)-phenyl]-2-fluoro-benzamide 541 414 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-benzo[1,3]dioxol-5-ylmethyl- thioureido)-phenyl]-amide 542 506[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 543 516N-{4-[3-(3,5-Bis-trifluoromethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 544 352 Furan-2-carboxylic acid[4-(3-benzyl-thioureido)-phenyl]-amide 545 421 Furan-2-carboxylic acid{4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}- amide 546 396Furan-2-carboxylic acid [4-(3-benzo[1,3]dioxol-5-ylmethyl-thioureido)-phenyl]-amide 547 488 Furan-2-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-benzyl)- thioureido]-phenyl}-amide 548503 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-bromo-3-trifluoromethyl- phenyl)-thioureido]-phenyl}-amide 549529 N-{4-[3-(3-Bromo-4-trifluoromethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 550 519 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-bromo-4-trifluoromethoxy- phenyl)-thioureido]-phenyl}-amide 551473 Furan-2-carboxylic acid{4-[3-(3-chloro-4-trifluoromethylsulfanyl-phenyl)-thioureido]-phenyl}-amide 552 4122-Fluoro-N-(4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 553 4122-Fluoro-N-(4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 554 402 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3[2-(3-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide 555 402[1,2,3]Thiadiazole-4-carboxylic acid (4-{3[2-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 556 495 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(2-methyl-butyl)-5-trifluoro-methyl-phenyl]-thioureido}-phenyl)-amide 557 481[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-isobutyl-5-trifluoromethyl- phenyl)-thioureido]-phenyl}-amide558 523 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(4-methyl-piperazin-1-yl)-5-trifluoro-methyl-phenyl]-thioureido}-phenyl)-amide 559 510[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-morpholin-4-yl-5-trifluoro-methyl-phenyl)-thioureido]-phenyl}-amide 560 494[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-pyrrolidin-1-yl-5-trifluoro-methyl-phenyl)-thioureido]-phenyl}-amide 561 384 Furan-2-carboxylic acid(4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide 562 419[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro-phenyl)-ethyl]-thioureido]-phenyl)-amide 563 429N-(4-{3-[2-(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 564 401 Furan-2-carboxylic acid(4-{3-[2-(3-chloro-phenyl)-ethyl]-thioureido}- phenyl)-amide 565 402[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 566 5042-Fluoro-N-{4-[3-(3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 567 477N-{4-[3-(3-Dimethylamino-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 568 5202-Fluoro-N-{4-[3-(3-morpholin-4-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 569 5332-Fluoro-N-(4-{3-[3-(4-methyl-piperazin-1-yl)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-benzamide 570 5182-Fluoro-N-{4-[3-(3-piperidin-1-yl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 571 468 [1,2,3]Thiadiazole-4-carboxylicacid {4-[3-(3-dimethylamino-5-trifluoro-methyl-phenyl)-thioureido]-phenyl}-amide 572 405[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-benzyl)-thioureido]- phenyl}-amide 573 384Furan-2-carboxylic acid (4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 574 366 Furan-2-carboxylic acid[4-(3-phenethyl-thioureido)-phenyl]-amide 575 384[1,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenethyl-thioureido)-phenyl]-amide 576 3942-Fluoro-N-[4-(3-phenethyl-thioureido)-phenyl]-benzamide 577 5052-Fluoro-N-(4-{3-[3-(2-methyl-butyl)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-benzamide 578 4912-Fluoro-N-{4-[3-(3-isobutyl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 579 388 Furan-2-carboxylic acid{4-[3-(3,5-difluoro-benzyl)-thioureido]-phenyl}- amide 580 416N-{4-[3-(3,5-Difluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 581406 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-difluoro-benzyl)-thioureido]-phenyl}-amide 582 421 Furan-2-carboxylic acid{4-[3-(3,5-dichloro-benzyl)-thioureido]-phenyl}- amide 583 449N-{4-[3-(3,5-Dichloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 584439 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-benzyl)-thioureido]-phenyl}-amide 585 438 Furan-2-carboxylic acid{4-[3-(3-fluoro-5-trifluoromethyl-benzyl)- thioureido]-phenyl}-amide 586466 2-Fluoro-N-{4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-benzamide 587 456 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-fluoro-5-trifluoromethyl- benzyl)-thioureido]-phenyl}-amide 588384 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(1-phenyl-ethyl)-thioureido]- phenyl}-amide 589 3942-Fluoro-N-{4-[3-(1-phenyl-ethyl)-thioureido]-phenyl}-benzamide 590 366Furan-2-carboxylic acid {4-[3-(1-phenyl-ethyl)-thioureido]-phenyl}-amide591 4122-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 592 384 Furan-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide 593 413N-{4-[3-(1-tert-Butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-2-fluoro-benzamide 594 510 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(isobutyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 595 510[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(3-hydroxy-pyrrolidin-1-yl)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 596 5202-Fluoro-N-(4-{3-[3-(isobutyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-benzamide 597 510 [1,2,3]Thiadiazole-4-carboxylicacid (4-{3-[3-(butyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 598 520N-(4-{3-[3-(Butyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 599 520 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,5-bis-trifluorometyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 600 442[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 601 522[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-piperidin-1-yl-3-trifluoro-methyl-benzyl)-thioureido]-phenyl}-amide 602 482[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-dimethylamino-3-trifluoro-methyl-benzyl)-thioureido]-phenyl}-amide 603 381 Furan-2-carboxylic acid(4-{3-[2-(4-amino-phenyl)-ethyl]-thioureido}- phenyl)-amide 604 445Furan-2-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 605 380 Furan-2-carboxylic acid{4-[3-(2-p-tolyl-ethyl)-thioureido]-phenyl}-amide 606 463[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 607 396 Furan-2-carboxylic acid(4-{3-[2-(3-methoxy-phenyl)-ethyl]-thioureido}- phenyl)-amide 608 403[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-tert-butyl-1H-imidazol-2-yl)-thioureido]-phenyl}-amide 609 384 Furan-2-carboxylic acid{4-[3-(1-tert-butyl-1H-imidazol-2-yl)-thiouredio]- phenyl}-amide 610 492N-{4-[3-(4-Dimethylamino-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 611 427 Furan-2-carboxylic acid(4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]- thioureido}-phenyl)-amide 612380 Furan-2-carboxylic acid {4-[3-(3-phenyl-propyl)-thioureido]-phenyl}-amide 613 399 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-phenyl-propyl)-thioureido]- phenyl}-amide 614 502Furan-2-carboxylic acid (4-{3[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 615 550 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-iodo-3-trifluoromethyl- phenyl)-thioureido]-phenyl}-amide 6165322-Fluoro-N-{4-[3-(4-piperidin-1-yl-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-benzamide 617 537 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-benzyl]-thioureido}-phenyl)-amide 618 482[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5-trifluoro-methyl-benzyl)-thioureido]-phenyl}amide 619 488 Furan-2-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido- methyl]-phenyl}-amide620 421 Furan-2-carboxylic acid{4[3-(3,5-dichloro-phenyl)-thioureidomethyl]- phenyl}-amide 621 421Furan-2-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureidomethyl]-phenyl}-amide 622 455 Furan-2-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido-methyl]-phenyl}-amide 623 4662-Fluoro-N-{4-[3-(4-fluoro-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-benzamide 624 446 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-fluoro-3-trifluoromethyl- benzyl)-thioreido]-phenyl}-amide 625410 2-Fluoro-N-{4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl}-benzamide 626382 Furan-2-carboxylic acid {4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl}-amide 627 400 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-phenoxy-ethyl)-thioureido]- phenyl}-amide 628 4092-Fluoro-N-{4-[3-(3-phenyl-propyl)-thioureido]-phenyl}-benzamide 629 425[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-trifluoromethyl-pyridin-3-yl)-thioureido]-phenyl}-amide 630 439 [1,2,3]Thiadiazole-4-carboxylicacid {4-[3-(3,4-dichloro-phenyl)- thioureido-methyl]-phenyl}-amide 631473 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureidomethyl]-phenyl}-amide 632 3812-Fluoro-N-[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-benzamide 633353 Furan-2-carboxylic acid[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]- amide 634 371[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-pyridin-3-ylmethyl-thioureido)- phenyl]-amide 635 439[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido-methyl]-phenyl}-amide 636 492N-{4-[3-(3-Dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 637 415 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-methoxy-phenyl)-ethyl]- thioureido}-phenyl)-amide 638 399[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-p-tolyl-ethyl)-thioureido]- phenyl}-amide 639 445[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]-thioureido}-phenyl)-amide 640 506 [1,2,3]Thiadiazole-4-carboxylicacid {4-[3-(3,5-trifluoromethyl- phenyl)-thioureidomethyl]-phenyl}-amide641 516N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureidomethyl]-phenyl}-2-fluoro-benzamide 642 449N-{4-[3-(3,5-Dichloro-phenyl)-thioureidomethyl]-phenyl}-2-fluoro-benzamide 643 449N-{4-[3-(3,4-Dichloro-phenyl)-thioureidomethyl]-phenyl}-2-fluoro-benzamide 644 448 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-acetylamino-5-chloro- phenyl)-thioureido]-phenyl}-amide 645 453[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-dichloro-phenyl)-ethyl]- thioureido}-phenyl)-amide 646 413[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-methyl-3-phenyl-propyl)-thioureido]-phenyl}-amide 647 463 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]- thioureido}-phenyl)-amide 648 413[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-phenyl-butyl)-thioureido]-phenyl}-amide 649 397 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-indan-1-yl-thioureido)-phenyl]- amide 650 400[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-methoxy-benzyl)-thioureido]-phenyl}-amide 651 415 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-methoxy-phenyl)-ethyl- thioureido}-phenyl)-amide 652 415[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-methoxy-phenyl)-ethyl]-thioureido}phenyl)-amide 653 506N-(4-{3-[2-(3-Dimethylamino-5-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 654 510[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-(3-dimethylamino-propyl)-5-trifluoromethyl-phenyl]-thioureido}-phenyl)-amide 655 417[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl}-amide 656 4272-Fluoro-N-{4-[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl}-benzamide657 399 Furan-2-carboxylic acid{4-[3-(2-phenylsulfanyl-ethyl)-thioureido]- phenyl}-amide 658 3812-Fluoro-N-[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-benzamide 659353 Furan-2-carboxylic acid[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]- amide 660 371[1,2,3]Thiadiazole-4-carboxylic acid[4-(3-pyridin-4-ylmethyl-thioureido)- phenyl]-amide 661 5062-Fluoro-N-{4-[3-(3-iodo-benzyl)-thioureido]-phenyl}-benzamide 662 478Furan-2-carboxylic acid {4-[3-(3-iodo-benzyl)-thioureido]-phenyl}-amide663 496 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-iodo-benzyl)-thioureido]- phenyl}-amide 664 479N-(4-{3-[2-(3,5-Dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 665 451 Furan-2-carboxylic acid(4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]- thioureido}-phenyl)-amide 666445 N-(4-{3-[2-(3-Chloro-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 667 417 Furan-2-carboxylic acid(4-{3-[2-(3-chloro-phenoxy)-ethyl]-thioureido}- phenyl)-amide 668 435[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 669 4662-Fluoro-N-{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-benzamide 670 438 Furan-2-carboxylic acid{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)- thioureido]-phenyl}-amide 671456 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-fluoro-5-trifluoromethyl- benzyl)-thioureido]-phenyl}-amide 672416 N-{4-[3-(3,4-Difluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide673 452 N-(4-{3-[2-(4-Dimethylamino-3-methyl-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 674 496 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-dimethylamino-50trifluoro-methyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 675 388Furan-2-carboxylic acid {4-[3-(3,4-difluoro-benzyl)-thioureido]-phenyl}-amide 676 406 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4-difluoro-benzyl)- thioureido]-phenyl}-amide 677 433N-{4-[3-(3-Chloro-4-fluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 678 495 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-phenylsulfanyl)- ethyl]-thioureido}-phenyl)-amide 679477 Furan-2-carboxylic acid (4-{3-[2-(3-bromo-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide 680 505N-(4-{3-[2-(3-Bromo-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 681 493 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-4-methoxy- phenyl)-ethyl]-thioureido}-phenyl)-amide682 493 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(5-bromo-2-methoxy- phenyl)-ethyl]-thioureido}-phenyl)-amide683 419 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-chloro-phenyl)-ethyl]- thioureido}-phenyl)-amide 684 402[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 685 419 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-chloro-phenyl)-ethyl]- thioureido}-phenyl)-amide 686 475[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,3-diphenyl-propyl)-thioureido]-phenyl}-amide 687 5472-Fluoro-N-(4-{3-[4-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-benzyl]-thioureido}-phenyl)-benzamide 688 469[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]-thiorueido}-phenyl)-amide 689 423 [1,2,3]Thiadiazole-4-carboxylicacid {4-[3-(3-chloro-4-fluoro-benzyl)- thioureido]-phenyl}amide 690 427[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-tert-butyl-benzyl)-thioureido]-phenyl}-amide 691 399 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dimethyl-benzyl)- thioureido]-phenyl}-amide 692 442[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-dimethylamino-3-methyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 693 479[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromo-phenoxy)-ethyl]-thioureido}-phenyl)-amide 694 526 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-iodo-phenoxy)-ethyl]- thioureido}-phenyl)-amide 695 489N-(4-{3-[2-(4-Bromo-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 696 5362-Fluoro-N-(4-{3-[2-(4-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-benzamide 697 461 Furan-2-carboxylic acid(4-{3-[2-(4-bromo-phenoxy)-ethyl]-thioureido}- phenyl)-amide 698 508Furan-2-carboxylic acid (4-{3-[2-(4-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-amide 699 408 Oxazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]- phenyl}-amide 700 424Thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 701 491 Thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide 702408 Oxazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 703 469 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-dichloro-phenoxy)- ethyl]-thioureido}-phenyl)-amide 704424 Thizaole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 705 458 Thiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide 706400 [1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenylamino-ethyl)-thioureido]-phenyl}-amide 707 453 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2,4-dichloro-phenyl)-ethyl]- thioureido}-phenyl)-amide 708 452[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-trifluoromethyl-phenyl)- ethyl]-thioureido}-phenyl)-amide709 453 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2,6-dichloro-phenyl)-ethyl]- thioureido}-phenyl)-amide 710 485[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide 711 503[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-5-trifluoromethyl-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide 712 668N-(4-{3-[3-Chloro-5-(3-{4-[([1,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-phenyl]-thioureido}-phenyl)-[1,2,3]thiadiazole-4-carboxamide 713 413 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-ethyl-phenyl)-ethyl]- thioureido}-phenyl)-amide 714 442Oxazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 715 475 Oxazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide 716420 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,4-difluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide 717 452[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-trifluoromethyl-phenyl)- ethyl]-thioureido}-phenyl)-amide718 435 Furan-2-carboxylic acid(4-{-[2-(3,4-dichloro-phenyl)-ethyl]-thioureido}- phenyl)-amide 719 463N-(4-{3-[2-(3,4-Dichloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 720 420 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3,5-difluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide 721 4122-Fluoro-N-(4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 722 429 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-nitro-phenyl)-ethyl]- thioureido}-phenyl)-amide 723 399[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(1-methyl-2-phenyl-ethyl)-thioureido]-phenyl}-amide 724 437N-{4-[3-(4-tert-Butyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 725409 N-{4-[3-(3,5-Dimethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide726 400 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-hydroxy-1-phenyl-ethyl)- thioureido]-phenyl}-amide 727 4092-Fluoro-N-{4-[3-(1-methyl-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide 728 399 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(1-methyl-1-phenyl-ethyl)- thioureido]-phenyl}-amide 729 405[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-chloro-benzyl)-thioureido]- phenyl}-amide 730 388[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-fluoro-benzyl)-thioureido]- phenyl}-amide 731 438[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide 732 388 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-fluoro-benzyl)-thioureido]- phenyl}-amide 733 435[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-chloro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 734 479 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-bromo-phenoxy)-ethyl]- thioureido}-phenyl)-amide 735 418[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-phenoxy)-ethyl]-thioureido}-phenyl)-amide 736 418 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-fluoro-phenoxy)-ethyl]- thioureido}-phenyl)-amide 737 486[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(2-fluoro-5-trifluoromethyl-phenoxy)-ethyl]-thioureido}-phenyl)-amide 738 384 Furan-2-carboxylicacid (4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide 739435 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-bromo-phenyl)-thioureido]- phenyl}-amide 740 374[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-fluoro-phenyl)-thioureido]- phenyl}-amide 741 388[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-fluoro-benzyl)-thioureido]- phenyl}-amide 742 405[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-benzyl)-thioureido]- phenyl}-amide 743 449[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-benzyl)-thioureido]-phenyl}-amide 744 332N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-acetamide 745438 Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}-amide 746 455 Thiazole-4-carboxylic acid{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)- thioureido]-phenyl}-amide 747426 Thiazole-4-caboxylic acid {4-[3-(4-tert-butyl-benzyl)-thioureido]-phenyl}-amide 748 374 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-fluoro-phenyl)-thioureido]- phenyl}-amide 749 374[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-fluoro-phenyl)-thioureido]- phenyl}-amide 750 526[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-amide 751 409N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thoureido}-phenyl)-2-phenyl-acetamide 752 425N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide 753 425N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-3-methoxy-benzamide 754 425N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-methoxy-benzamide 755 4292-Chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 756 4294-Chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 757 453 Acetic acid4-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl-carbamoyl)-phenyl ester 758 394N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 759395N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-isonicotinamide760 410N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-hydroxy-benzamide 761 4293-Chloro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 762 470 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 763 520[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 764 470[1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 765 4384-Dimethylamino-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 766 470 [1,2,3]Thiadiazole-4-carboxylic acid(4{3-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 767 470[1,2,3]Thiadiazole-4-carboxylic acid(4{3-[2-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 768 510[1,2,3]Thiadiazole-4-carboxylic acid (4{3-[2-(3-iodo-phenyl)-ethyl]-thioureido}-phenyl)-amide 769 470 [1,2,3]Thiadiazole-4-carboxylic acid(4{3-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 770 463[1,2,3]Thiadiazole-4-carboxylic acid (4{3-[2-(3-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 771 4272-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-propyl]-thioureido}-phenyl)-benzamide 772 4752-Fluoro-N-(4-{3-[(4-fluoro-phenyl)-phenyl-methyl]-thioureido}-phenyl)-benzamide 773 4552-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-pentyl]-thioureido}-phenyl)-benzamide 774 4892-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-2-phenyl-ethyl]-thioureido}-phenyl)-benzamide 775 4092-Fluoro-N-{4-[3-(1-o-tolyl-ethyl)-thioureido]-phenyl}-benzamide 776 4092-Fluoro-N-{4-[3-(1-m-tolyl-ethyl)-thioureido]-phenyl}-benzamide 777 4252-Fluoro-N-(4-{3-[1-(4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 778 4122-Fluoro-N-(4-{3-[1-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 779 429N-(4-{3-[1-(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 780 473N-(4-{3-[1-(3-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 781 429N-(4-{3-[1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 782 4092-Fluoro-N-{4-[3-(1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide 783 473N-(4-{3-[1-(2-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 784 429N-(4-{3-[1-(2-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 785 4622-Fluoro-N-(4-{3-[1-(2-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 786 4622-Fluoro-N-(4-{3-[1-(3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 787 4622-Fluoro-N-(4-{3-[1-(4-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 788 4252-Fluoro-N-(4-{3-[1-(2-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 789 4252-Fluoro-N-(4-{3-[1-(3-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 790 4412-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-2-methyl-propyl]-thioureido}-phenyl)-benzamide 791 419N-(4-{3-[1-(3-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 792 419N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 793 438N-(4-{3-[1-(4-Dimethylamino-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 794 438N-(4-{3-[1-(3-Dimethylamino-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 795 4732-Bromo-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 796 446 Quinoline-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide 797 4102-Fluoro-N-{4-[3-(2-hydroxy-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide 798 3322-Fluoro-N-[4-(3-isopropyl-thioureido)-phenyl]-benzamide 799 4452-Fluoro-N-{4-[3-(1-naphthalen-2-yl-ethyl)-thioureido]-phenyl}-benzamide 800 4123-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 801 4124-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 802 3842-Fluoro-N-{4-[3-(1-furan-2-yl-ethyl)-thioureido]-phenyl}-benzamide 8033952-Fluoro-N-{4-[3-(1-pyridin-4-yl-ethyl)-thioureido]-phenyl}-benzamide804 3972-Fluoro-N-(4-{3-[1-(1-methyl-1H-pyrrol-2-yl)-ethyl]-thioureido}-phenyl)-benzamide 805 4012-Fluoro-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}- benzamide806 445 N-{4-[3-(3-Chloro-4-ethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 807 459N-{4-[3-(3-Chloro-4-propoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 808 459N-{4-[3-(3-Chloro-4-isopropoxy-phenyl)-thioureido]-phenyl}-2-fluoro-Benzamide 809 473N-{4-[3-(4-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 810 5222-Fluoro-N-{4-[3-(3-iodo-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide 811 475N-{4-[3-(3-Bromo-4-methoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 812 520N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-iodo-benzamide 813 346N-(4-{3[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-propionamide 814286 N-[4-(3-Phenyl-thioureido)-phenyl]-acetamide 815 463[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(1S)-1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 816 463 [1,2,3]Thiadiazole-4-carboxylicacid (4-{3-[(1R)-1-(4-bromo-phenyl)- ethyl]-thioureido}-phenyl)-amide818 520 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 820 418[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(1S)-1-(4-chloro-phenyl)-ethyl]-thioureido}-phenyl)-amide 821 418 [1,2,3]Thiadiazole-4-carboxylicacid (4-{3-[(1R)-1-(4-chloro-phenyl)- ethyl]-thioureido}-phenyl)-amide822 409N-[4-[[[[1-(4-Cyanophenyl)ethyl]amino]thioxomethyl]amino]phenyl]-1,2,3-thiadiazole-4-carboxamide 824 462 Thiazole-4-caboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}- phenyl)-amide 825 520[1,2,3]Thiadiazole-4-carboxylic acid (4-{3-[(1S)-[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)-amide 828 470N-(4-{[({1-[4-fluoro-3-trifluoromethyl)phenyl]-ethyl}amino)carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide 829 486N-(4-{[({1-[4-chloro-3-hiadiazole-4-carboxamide 830 519N-(4-{[({(1S)-1-[3,5-thiazole-4-carboxamide 831 469N-(4-{[({1-[3-fluoro-5-trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide 832 469N-(4-{[({1-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide 833 469N-(4-{[({1-[2-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide 834 519N-(4-{[({1-[2,4-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide 834 411N-{4-[({[1-(2,4-dimethylphenyl)ethyl]amino}carbothioyl)amino9 phenyl}-1,3-thiazole-4-carboxamide 836 452N-{4-[({[1-(2,4-dichlorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide 837 397N-{4-[({[1-(3-methylphenyl)-ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide 838 469N-(4-{[({1-[4-fluoro-3-trifluoromethyl)phenyl]ethyl}-amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide 839 435N-{4-[({[1-(2-chloro-4-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide 840 419N-{4-[({[1-(3,4-difluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide 841 480 N-{4-[({[1-(4-bromo-2-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole4-carboxamide 842 401N-{4-[({[1-(3-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide 843 462N-{4-[({[1-(2-bromophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide 844 462N-{4-[({[1-(2-bromophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide 845 451 N-(4-{[({1-[2-(trifluoromethyl)-phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide 846 419N-{4-[({[1-(2,4-difluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide 847 519N-(4-{[({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide 848 452N-{4-[({[1-(3,4-dichlorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide 849 469N-(4-{[({1-[3-fluoro-4-trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide 850 845N-(4-{[({1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide 851 435N-{4[({[1-(4-chloro-2-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide 852 469N-(4-{[({1-[4-fluoro-2-trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide 853 435N-{4-[({[1-(4-chloro-3fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl{-1,3-thiazole-4-carboxamide 854 480 N-{4-[({[1-(2-bromo-4fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl{-1,3-thiazole-4-carboxamide 855 541N-{4-[({[1-(3,4-dibromophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide 856 435 N-{4-[({[1-(3-chloro-4-fluorophenyl)ethyl]amino}carbothioyl)amno]phenyl}-1,3-thiazole-4-carboxamide 857 366N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide 858 392N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]butyl}amino)carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide 859 330N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]pentyl}amino)carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide 860 521N-{4-[({[[3,5-bis(trifluoromethyl)phenyl](phenylmethyl]amino}carbothioyl)amino]phenyl}-1,2,3-thiadiazole-4-carboxamide 861 450N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]-1-methylethyl}amino)carbothioyl]amino}phenyl)-1,2,3-thiadiazole-4-carboxamide 862 433N-{4-[({[3,5-bis(trilfluoromethyl)benzyl]amino}carbothioyl)amino]phenyl}-1H-imidazole-4-carboxamide 863 440N-{4-[({[1-(4-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1H-imidazole-4-carboxamide 864 506 N-{4-[({[3,5-bis(trifluoromethyl)benzyl]amino}carbothioyl)amino]phenyl}-1-methyl-1H-imidazole-4-carboxamide 865 462N-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide

EXAMPLE 866 METHOD 32 [1,2,3]Thiadiazole-4-carboxylic Acid{4-[3-(2,5-dichloro-phenyl)-thioureido]-phenyl}-amide

To a solution of 2,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL)is added freshly prepared 1,1′-thiocarbonyldiimidazole (0.20 g) and themixture is stirred for approximately 30 minutes at room temperature.[1,2,3]-Thiadiazole-4-carboxylic acid (4-amino-phenyl)amide (0.22 g) isadded to the reaction flask and the mixture is stirred for approximately6 hours. The solvent is then removed by evaporation under reducedpressure and warm acetonitrile (3 mL) is added. After 15 hours themixture is filtered and the collected precipitate is washed withacetonitrile then diethyl ether, and air dried to provide the desiredproduct as a white powder.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

EX. NO. M + H COMPOUND NAME 867 321N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-acetamide 868 413N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide 869443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-methoxy-benzamide 870 443N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide 871 443N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}4-methoxy-benzamide 872 431N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide 873 431N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide 874 431N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-fluoro-benzamide 875 437 Furan-2-carboxylic acid{4-[3-(3,5-dichloro-4-methoxy-phenyl) thioureido]-phenyl}-amide 876 511{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acidhexyl ester 877 481 Hexanoic acid{4-[3-(5-bromo-2,4-dimethoxy-phenyl)-Thioureido]- phenyl}-amide 878 505N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 879 477 Furan-2-carhoxylic acid{4-[3-(5-bromo-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide 880 501N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2methyl-benzamide 881 517N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide 882 395N-{4-[3-(5-Chloro-2-ethoxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 883 395N-{4-[3-(5-Chloro-4-ethoxy-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide 884 423N-{4-[3-(2-Butoxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl)}-acetamide 885 423N-{4-[3-(4-Butoxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide 886 457N-{4-[3-(2-Benzyloxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 887 457N-{4-[3-(4-Benzyloxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide 888 421 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-methoxy- phenyl)-thioureido]-phenyl}-amide 889 4242-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-acetamide 890 367N-{4-[3-(5-Chloro-2-hydroxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide 891 367N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-acetamide 892 447N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-piperidin4-yl)-amino]-phenyl}-thioureido)-phenyl]-acetamide 893 426N-(4-{3-[3-Chloro-4-(methyl-phenyl-amino)-phenyl]-thioureido}-phenyl)-acetamide 894 509N-[4-(3-{4-[(1-Benzo-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-acetamide 895 418N-(4-{3-[3-Chloro-4-(cyclopentyl-methyl-amino)-phenyl]-thioureido}-phenyl)-acetamide 896 433N-[4-(3-{3-Chloro-4-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-acetamide 897 419 Furan-2-carhoxylic acid{4-[3-(3-chloro-4-methylsulfanyl-phenyl) thioureido]-phenyl}-amide 898447 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 899 465N-∴4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2,6-difluoro-benzamide 900 445N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 901 441N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-methyl-benzamide 902 434 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-dimethylamino- phenyl)-thioureido]-phenyl}-amide 903444 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 904 517 [1,2,3]Thiadiazole-4-carboxylic acid[4-(3-{3-chloro-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-amide 905 579[1,2,3]Thiadiazole-4-carboxylic acid [4-(3-{4-[(1-benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-amide 906 527N[4-(3-{3-Chloro-4-[methyl-piperidin-4-yl)-amino]-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 907 435[1,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-amide 908 589N-[4-(3-{4-[(1-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-2-fluoro-benzamide 909 501 Furan-2-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido)]-3-trifluoromethyl-phenyl}-amide 910 3662-Fluoro-N-[4-(3-phenyl-thioureido)-phenyl]-benzamide 911 338Furan-2-carboxylic acid [4-(3-phenyl-thioureido)-phenyl)-amide 912 356[1,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenyl-thioureido)-phenyl]-amide 913 365N-(4{3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-acetamide 914 435 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(1-hydroxy- ethyl)-phenyl]-thioureido}-phenyl)-amide915 365N-4-{3-[3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-acetamide 916 445N-(4-{3-[3-Chloro-4-(1-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 917 417 Furan-2-carboxylic aCID(4-{3-[3-chloro-4-(1-hydroxy-ethyl)-phenyl]- thioureido}-phenyl)-amide918 371 [1,2,3]Thiadiazole-4-carboxylic aicd {4-[3-(3-amino-phenyl)-thioureido]-phenyl}-amide 919 501 Furan-2-carboxylic acid{4-[3-(3-bromo-4-trifluoromethoxy-phenyl)- thioureido]-phenyl}-amide 920423 N-{4-[3-(3-tert-Butyl-phenyl)-thioureido -phenyl}-2-fluoro-benzamide1025 440 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-3,5-dichloro- phenyl)-thioureido]-phenyl}-amide 1026 485N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-trifluoromethyl-benzamide 1027 412N-(4-Fluoro-phenyl)-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-benzamide 1028 446 Isoquinoline-1-carboxylic acid(4{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide 1029 468Isoquinoline-1-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-phenyl}-amide 1030 506 Isoquinoline-1-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]- thioureido}-phenyl)-amide 1031 453Isoquinoline-1-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-amide 1032 435 Benzofuran-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide 1033 457Benzofuran-2-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-phenyl}-amide 1034 495 Benzofuran-2-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]- thioureido}-phenyl)-amide 1035 442Benzofuran-2-carboxylic acid (4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-amide 1036 446 Isoquinoline-3-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide 1037 468Isoquinoline-3-carboxylic acid {4-[3-(1-benzofuran-2-yl-ethyl)-thioureido]-phenyl}-amide 1038 453 Isoquinoline-3-carboxylic acid(4-{3-[1-(4-cyano-phenyl)-ethyl]- thioureido}-phenyl)-amide 1039 506Isoquinoline-3-carboxylic acid (4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide 1040 446 Quinoline-3-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide 1041 446Quinoline-4-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1042 446 Quinoline-6-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide 1043 446Quinoline-8-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1044 462N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-trifluoromethyl-benzamide 1045 4192-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 1046 473N-{4-[3-(3-Chloro-4-isobutyoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 1047 4142-Fluoro-N-{4-[3-(3-fluoro-4-methxy-phenyl)-thioureido]-phenyl}-benzamide 1048 475N-(4-{3-[3-Chloro-4-(2-methoxy-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 1049 3982-Fluoro-N-{4-[3-(3-fluoro-4-methyl-phenyl)-thioureido]-phenyl}-benzamide 1050 4642-Fluoro-N-{4-[3-(4-methoxy-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 1051 449N-{4-[3-(2-Amino-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 1052 459N-(4-{3-[1-(3-Chloro-4-methoxy-phenyl)-etjhyl]-thioureido}-phenyl)-2-fluoro-benzamide 1053 417N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl)-2-fluoro-benzamide 1054 435N{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-fluoro- benzamide1055 4482-Fluoro-N-{4-[3-(4-methyl-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-benzamide 1056 473(S)-N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1057 473N-(4-{3-[(1R)-1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1058 4942-Fluoro-N-(4-{3-[2-methoxy-4-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-benzamide 1059 399N-{4-[3-(2-Amino-5-fluoro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 1060 502N-(4-{3-[1-(4-Dimethylsulfamoyl-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1061 5422-Fluoro-N-[4-(3-{1-[4-(piperidine-1-sulfonyl)-phenyl]-ethyl}-thioureido)-phenyl]-benzamide 1062 562n-(4-{3-[2,4-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro-benzamide 1063 4092-Fluoro-N-{4-[3-((1S)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide1064 4092-Fluoro-N-{4-[3-((1R)-1-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide1065 3942-Fluoro-N-{4-[3-((1S)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide1066 429N-(4-{3-[(1R)-1-(4-Chloro-phenyl)-ethyl]-thioureido]-phenyl)-2-fluoro-benzamide 1067 429N-(4-{3-[(1S)-1-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1068 3942-Fluoro-N-{4-[3-((1R)-1-phenyl-ethyl)-thioureido]-phenyl}-benzamide1069 432N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide 1070 447N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thiouredo]-phenyl}-2-methoxy-benzamide 1071 485N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide 1072 4193-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 1073 462N-(4-{3-[1-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-trifluoromethyl-benzamide 1074 4194-Cyano-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 1075 4692-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2,3,4,6-tetramethyl-phenyl)-benzamide 1076 480N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2,5-dimethoxy-phenyl)-2-fluoro-benzamide 1077 4732-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2,5-dimethoxy-phenyl)-benzamide 1078 530N-{3,5-Dichloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 1079 447N-(3-Chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1080 4802,3,4,5-Tetrafluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)-benzamide 1081 4622,4,5-Trifluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)-benzamide 1082 4272-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)-benzamide 1083 4572-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methoxy-5-methyl-phenyl)-benzamide 1084 4432-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methoxy-phenyl)-benzamide 1085 570N-(2,6-Dibromo-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1086 4802-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-benzamide 1087 541N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thiouredio}-2-trifluoromethyl-phenyl)-2-fluoro-benzamide 1088 487N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-2-fluoro-benzamide 1089 503N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-trifluoromethyl-phenyl}-2-fluoro-benzamide 1090 447N-(2-Chloro-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1091 454N-(2-Chloro-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1092 437N-(2-Cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1093 498N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-cyano-phenyl)-2-fluoro-benzamide 1094 445N-(2-Cyano-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1095 460N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-cyano-phenyl}-2-fluoro-benzamide 1096 517N-(2-Benzoyl-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1097 4272-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-benzamide 1098 487N-(4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2-fluoro-benzamide 1099 434N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2-fluoro-benzamide 1100 449N-{4-[3-(1-Benzofuran-2-yl-ethyl)-thioureido]-2-methyl-phenyl}-2-fluoro-benzamide 1101 456N-(2-Dimethylamino-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1102 526N-(2-Benzyloxy-4-{3-[1-(4-cyano-phenyl)-etyl]-thioureido}-phenyl)-2-fluoro-benzamide 1103 519N-(2-Benzyloxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1104 603N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy)-phenyl]-2-fluoro-benzamide 1105 603N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy)-phenyl]-2-fluoro-benzamide 1106 5422-Fluoro-N-[4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide 1107 485N-(2-Butoxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}}-phenyl)-2-fluoro-benzamide 1108 4924-(2-Butoxy-4-{3-[1-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1109 589N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido)-2-(2-diethylamino-ethoxy)-phenyl]-2-fluoro-benzamide 1110 528N-(2-(2-Diethylamino-ethoxy)-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1111 589N-[4-{3-[1-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-ethoxy)-phenyl]-2-fluoro-benzamide 1112 457N-(2-Ethoxy-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide 1113 464N-(4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-ethoxy-phenyl)-2-fluoro-benzamide 1114 4682-Fluoro-N-[4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-(2-nitrilo-ethoxy)-phenyl]-benzamide 1115 475N-[4-{3-[1-(4-Cyano-phenyl)-ethyl]-thioureido}-2-(2-nitrilo-ethoxy)-phenyl]-2-fluoro-benzamide 1116 4432-Fluoro-N-(4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methoxy-phenyl)-benzamide 1117 4892-Fluoro-N-(50{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-biphenyl-2-yl)-benzamide 1118 514 Isoquinoline-1-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl-thioureido}-2-trifluoromethyl-phenyl)-amide 1119 503Benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-amide 1120 514Isoquinoline-3-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-amide 1121 471Isoquinoline-1-carboxylic acid (2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1122 460 Benzofuran-2-carboxylic acid(2-cyano-4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide1123 471 Isoquinoline-3-carboxylic acid(2-cyano-4-{3-[1-(4-fluoro-phenyl)- ethyl]-thioureido}-phenyl)-amide1124 460 Isoquinoline-1-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-2-methyl-phenyl)-amide1125 449 Benzofuran-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-amide 1126 460 Isoquinoline-3-carboxylicacid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-amide 1127 396 Pyrazine-2-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide 1128 401Thiophene-2-carboxylic acid (4-{3-[1-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-amide 1129 401 Thiophene-3-carboxylic acid(4-{3-[1-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide 1130 5002-Isopropyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1131 4662-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 1132 466 2-Isopropyl-thiazole-4-carboxylicacid {4-[3-(3,4-dichloro-phenyl)- thioureido]-phenyl}-amide 1133 5342-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1134 480 2-Butyl-thiazole-4-carboxylicacid {4-[3-(3,4-dichloro-phenyl)- thioureido]-phenyl}-amide 1135 5142-Butyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 1136 480 2-Butyl-thiazole-4-carboxylicacid {4-[3-(3,5-dichloro-phenyl)- thioureido]-phenyl}-amide 1137 5482-Butyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-thiouredio]-phenyl}amide 1138 438 2-Methyl-thiazole-4-carboxylicacid {4[3-(3,5-dichloro-phenyl)- thioureido]-phenyl}-amide 1139 4382-Methyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 1140 505 2-Methyl-thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl- phenyl)-thioureido]-phenyl}-amide 1141534 2-Phenyl-thiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl- phenyl)-thioureido]-phenyl}-amide1142 500 2-Phenyl-thiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)- thioureido]-phenyl}-amide 1143 5002-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 1144 568 2-Phenyl-thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl- phenyl)-thioureido]-phenyl}-amide 11454012-Fluoro-N-{4-[3-(1-thiazol-2-yl-ethyl)-thioureido]-phenyl}-benzamide1146 5882-Fluoro-N-[4-(3-{1-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-ethyl}-thioureido)-phenyl]-benzamide 1147 4462-Fluoro-N-{4-[3-(1-quinolin-2-yl-ethyl)-thioureido]-phenyl}-benzamide1148 4462-Fluoro-N-{4-[3-(1-quinolin-4-yl-ethyl)-thioureido]-phenyl}-benzamide1149 4462-Fluoro-N-{4-[3-(1-isoquinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide 1150 4462-Fluoro-N-{4-[3-(1-isoquinolin-1-yl-ethyl)-thioureido]-phenyl}-benzamide 1151 4462-Fluoro-N-{4-[3-(1-quinolin-6-yl-ethyl)-thioureido]-phenyl}-benzamide1152 4462-Fluoro-N-{4-[3-(1-quinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide1153 413 2-Methoxy-N-{4-[3-(1-thiophen-3-yl-ethyl)-thioureido]-phenyl}-benzamide

EXAMPLE 921 METHOD 33 [1,2,3]Thiadiazole-4-carboxylic Acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide

To a solution of 3,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 ml)is added freshly prepared 1,1′-thiocarbonyl-di-(1,2,4)-triazole (0.20 g)and the mixture is stirred for approximately 30 minutes at roomtemperature. [1,2,3]-Thiadiazole-4-carboxylic acid (4-amino-phenyl)amide(0.22 g) is added to the reaction flask and the mixture is stirred forapproximately 6 hours. The solvent is then removed by evaporation underreduced pressure and warm acetonitrile (3 mL) is added. After 15 hoursthe mixture is filtered and the collected precipitate is washed withacetonitrile then diethyl ether, and air dried to provide the desiredproduct as a white powder. [M+H] 424.

Using the above procedure and appropriate starting materials thefollowing compounds were prepared:

EX. NO. M + H COMPOUND NAME 922 465N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide923 477N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-methoxy-benzamide924 465N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide925 477N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide926 399N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-acetamide927 365N-{4-[3-(3-Chloro-4-methoxy-5-methyl-phenyl)-thioureido]-phenyl}-acetamide928 331 N-{4-[3-(2-Nitro-phenyl)-thioureido]-phenyl}-acetamide 929 331N-{4-[3-(4-Nitro-phenyl)-thioureido]-phenyl}-acetamide 930 477N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide931 351N-{4-[3-(2-Chloro-5-methoxy-phenyl)-thioureido]-phenyl}-acetamide 9324282-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetamide933 443{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy)-aceticacid methyl ester 934 457{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticacid ethyl ester 935 447N-{4-[3-(3,5-Dichloro-4-phenoxy-phenyl)-thioureido]-phenyl}-acetamide936 410N-(4-{3-[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide937 485{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-aceticacid tert-butyl ester 938 469 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,5-dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-amide 939 335N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 940 335N-{4-[3-(5-Chloro-2-methyl-phenyl)-thioureido]-phenyl}-acetamide 941 703N-{4-[3-(4-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyldisulfanyl3-chloro-phenyl)-thioureido]-phenyl}-acetamide 942 369N-{4-[3-(3,5-Dichloro-4-methyl-phenyl)-thioureido]-phenyl}-acetamide 943598N-{4-[3-(3,5-Diiodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide944 504N-{4-[3-(3,5-Dibromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide945 317 N-{4-[3-(6-Methoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide946 347N-{4-[3-(2,6-Dimethoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide 947457 Acetic acid2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-ethylester 948 365 4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-benzoicacid 949 346N-{4-[3-(3-Chloro-4-cyano-phenyl)-thioureido]-phenyl}-acetamide 950 512N-(4-{3-[5-Chloro-2-(4-chloro-phenoxy)-4-pyrrol-1-yl-phenyl]-thioureido}-phenyl)-acetamide951 355 N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 952339 N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl}-acetamide 953447 N-{4-[3-(3-Chloro-4-iodo-phenyl)-thioureido]-phenyl}-acetamide 954400 N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl}-acetamide 955424N-[4-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-3-chloro-phenyl}-thioureido)-phenyl]-acetamide956 434N-(4-{3-[3-Chloro-4-(hexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-acetamide957 406N-(4-{3-[3-Chloro-4-(isobutyl-methyl-amino)-phenyl]-thioureido}-phenyl)-acetamide958 389N-{4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide959 441 Furan-2-carboxylic acid{4-[3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide 960459 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide 961469N-{4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide962 435N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 963407 Furan-2-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 964 425[1,2,3]Thidiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide 965 480N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide966 527N-{4-[3-(3-Chloro-4-iodo-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide967 452 Furan-2-carboxylic acid{4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-phenyl}-amide 968 499Furan-2-carboxylic acid{4-[3-(3-chloro-4-iodo-phenyl)-thioureido]-phenyl}-amide 969 391Furan-2-carboxylic acid{4-[3-(3-chloro-4-fluoro-phenyl)-thioureido]-phenyl}-amide 970 470[1,2,3]Thiadiazole-4-carboxylic acid{4[3-(4-bromo-3-chloro-phenyl)-thioureido phenyl}-amide 971 517[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-iodo-phenyl)-thioureido]-phenyl}-amide 972 419N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide973 409 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-fluoro-phenyl)-thioureido]-phenyl}-amide 974 388N-{4-[3-(3-Chloro-4-isoxazol-5-yl-phenyl)-thioureido]-phenyl}-acetamide975 387N-(4-{3-[3-Chloro-4-(1H-pyrazol-3-yl)-phenyl]-thioureido}-phenyl)-acetamide976 355 N-{4-[3-(2,3-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 977435 N-{4-[3-(2,3-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-acetamide978 407 Furan-2-carboxylic acid{4-[3-(2,3-dichloro-phenyl)-thioureido]-phenyl}-amide 979 425[1,2,3]Thidiazole-4-carboxylic acid{4-[3-(2,3-dichloro-phenyl)-thioureido]-phenyl}-amide 980 355N-{4-[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 981 435N-{4-[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 982407 Furan-2-carboxylic acid{4-[3-(2,5-dichloro-phenyl)-thioureido]-phenyl}-amide 983 355N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}-acetamide 984 435N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 985407 Furan-2-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide 986 390N-{4-[3-(3,4,5-Trichloro-phenyl)-thioureido]-phenyl}-acetamide 987 4702-Fluoro-N-{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-benzamide988 442 Furan-2-carboxylic acid{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-amide 989 460[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-amide 990 458[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-isoxazol-5-yl-phenyl)- thioureido]-phenyl}-amide 991457 [1,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(1H-pyrazol-3-yl)-phenyl]- thioureido}-phenyl)-amide992 391 [1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-phenyl)-thioureido]-phenyl}-amide 993 373Furan-2-carboxylic acid{4-[3-(3-chloro-phenyl)-thioureido]-phenyl}-amide 994 401N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 995 373Furan-2-carboxylic acid{4-[3-(4-chloro-phenyl)-thioureido]-phenyl}-amide 996 401N-{4-[3-(4-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 997 391[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(4-chloro-phenyl)-thioureido]-phenyl}-amide 998 401N-{4-[3-(2-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 999 3963-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-benzoic acidmethyl ester 1000 4243-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid methylester 1001 4143-(3-{4-[([1,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-benzoicacid methyl ester 1002 409N-[4-[[[[3-(Aminocarbonyl)phenyl]amino]thioxomethyl]amino]phenyl]-2-fluoro-benzamide1003 373 Furan-2-carboxylic acid{4[3-(2-chloro-phenyl)-thioureido]-phenyl}-amide 1004 381Furan-2-carboxylic acid{4-[3-(3-carbamoyl-phenyl)-thioureido]-phenyl}-amide 1005 399[1,2,3]Thiadiazole-4-carboxylic acid{4[3-(3-carbamoyl-phenyl)-thioureido]-phenyl}-amide 1006 391[1,2,3]Thiadiazole-4-carboxylic acid{4-[3-(2-chloro-phenyl)-thioureido]-phenyl}amide 1007 356Furan-2-carboxylic acid{4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}-amide 1008 383Furan-2-carboxylic acid {4-[3-(3-nitro-phenyl)-thioureido]-phenyl}-amide1009 411 2-Fluoro-N-{4-[3-(3-nitro-phenyl)-thioureido]-phenyl}-benzamide1010 422 Furan-2-carboxylic acid{4-[3-(3-trifluoromethoxy-phenyl)-thioureido]-phenyl}-amide 1011 4502-Fluoro-N-{4-[3-(3-trifluoromethoxy-phenyl)-thioureido]-phenyl}-benzamide1012 3842-Fluoro-N-{4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}-benzamide 1013410 3-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid1014 382 3-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-benzoicacid 1015 408N-{4-[3-(3-Acetyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide 1016502N-{4-[3-(3-Butylsulfamoyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide1017 380 Furan-2-carboxylic acid{4-[3-(3-acetyl-phenyl)-thioureido]-phenyl}-amide 1018 447Furan-2-carboxylic acid (4-{3-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-thioureido}-phenyl)-amide 1019 4752-Fluoro-N-(4-{3-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-thioureido}-phenyl)-benzamide1020 474 Furan-2-carboxylic acid{4-[3-(3-butylsulfamoyl-phenyl)-thioureido]-phenyl}-amide

EXAMPLE 1021 METHOD 57 1-(4-Fluoro-phenyl)-2-methyl-propan-1-ol

To solution of 4-fluorobenzaldehyde (2.0 g) in diethyl ether (40 mL) at0° C. is added dropwise isopropylmagesium bromide (2.0 M, 9.6 mL) withstirring. After 1.5 hours the reaction is quenched with aqueous ammoniumchloride and extracted with diethyl ether. The diethyl ether extractsare washed with saturated sodium chloride, dried over anhydrousmagnesium sulfate, flitered and evaporated to give an oil. The oil ispurifed by silica gel chromatography eluting with 10%dichloromethane-hexanes to give the product, a yellow oil (1.76 g).

EXAMPLE 1022 METHOD 58 1-(4-Fluoro-phenyl)-2-methyl-propan-1-one

To a solution of 1-(4-Fluoro-phenyl)-2-methyl-propan-1-ol (1.6 g) inacetone (10 mL) at 0° C. is added Jones reagent (20 mL) with stirring.After 10 minutes excess Jones reagent is destroyed by addition ofisopropyl alcohol. Diethyl ether is added followed by anhydrousmagnesium and the mixture is filtered and evaporated to give theproduct, a yellow oil (1.2 g).

EXAMPLE 1023 METHOD 59 3-Dimethylamino-5-trifluoromethyl-benzonitrile

To a solution of 3-dimethylamino-5-trifluoromethylbromobenzene (7.3 g)in N,N-dimethylformamide (20 mL) is added cuprous cyanide (2.7 g) andthe reaction heated at reflux for 12 hours. The reaction is diluted withwater (40 mL) and dichloromethane is added. The dichloromethane fractionis washed with concentrated ammonium hydroxide, then water. The solutionis dried over anhydrous magnesium sulfate, filtered and concentrated togive a yellow solid which is recrystallized from hexanes to give ayellow solid, (4.7 g).

The foregoing compounds were tested for activity as herpes virusinhibitors.

HUMAN CYTOMEGALOVIRUS

Yield Assay

Monolayer cultures of human foreskin fibroblasts are infected with HCMVwild-type, typically at a multiplicity of infection equal to 0.2, in thepresence of inhibitor compound (varying concentrations). At three dayspost-infection, total virus produced in these cultures (i.e. virusyield) is assessed by harvesting and titering the virus in 12-wellplates of cultured human foreskin fibroblasts (done in the absence ofinhibitor). Plaques are quantified at 2 weeks post-infection. Aninhibitor of HCMV is identified by the reduction in titer of virus yieldin the presence, compared to the titer in the absence of compound. Inthis assay, the relative anti-HCMV activity of an inhibitor is typicallydetermined by calculating the IC₅₀ or IC₉₀ value, that is, the amount ofcompound required to reduce the virus yield by 50% or 90%, respectively.Table I describes IC₅₀ data for compounds tested against HCMV.

Microtiter Plate Assay

Ninety-six well plate cultures of human foreskin fibroblasts areinfected in the presence of inhibitor compound with a HCMV recombinantmutant virus whose genome contains the prokaryotic beta-glucuronidasegene (Jefferson, R. A., S. M. Burgess, and D. Hirsh. 1986.Beta-glucuronidase from Escherichia coli as a gene fusion marker. Proc.Natl. Acad. Sci. USA 83:8447-8451) whose expression is controlled by aviral promoter. An example of such a virus is RV145 (Jones, T. R., V. P.Muzithras, and Y. Gluzman. 1991. Replacement mutagenesis of the humancytomegalovirus genome: US10 and US11 gene products are nonessential. J.Virol. 65:5860-5872). Since it is under the control of a viral promoter,beta-glucuronidase expression is an indirect indicator of growth andreplication of HCMV in this assay. At 96 hours post-infection, theinfected cell lysates are prepared (using 50 mM sodium phosphate [pH7.0] containing 0.1% Triton X-100 and 0.1% sarkosyl) and assayed forbeta-glucuronidase activity using a substrate for the enzyme which whencleaved yields either a product which can be measured colorimetricallyin a spectrophotometer or fluorescently in a microfluorimeter. Examplesof such substrates are p-nitrophenyl-beta-D-glucuronide andmethylumbelliferylglucuronide, respectively. The presence of anantiviral compound is indicated by the reduced expression of the HCMVgenome resident beta-glucuronidase gene, compared to the absence ofinhibitor. Thus, the generation of the chromophore or fluorophoreproduct in this assay is correspondingly reduced. Data from this assaygenerated using varying amounts of inhibitor compound is also used toestimate the IC₅₀ of an inhibitor compound.

HSV Antiviral (ELISA) Assay

Vero cells (ATCC #CCL-81) are plated on 96-well tissue culture plates at3.5×10⁴ cells per 100 μl tissue culture DMEM (Dulbecco's modified Eaglemedia) supplemented with 2% fetal bovine serum (FBS) in each well. Afterovernight incubation @ 37° C. (in 5% CO₂) and 30 minutes prior toinfection with HSV-1 (multiplicity of infection equal to 0.006), cellsare either untreated, or treated with test compound (multipleconcentrations) or reference standard drug control. After approximately24 hours post-infection incubation @ 37° C. (in 5% CO₂), cells are fixedfor ELISA assay. The primary antibody is murine anti-HSV glycoprotein Dmonoclonal primary antibody and the secondary antibody is goatanti-mouse IgG linked to β-galactosidase. Thus the extent of viralreplication is determined by assessing β-galactosidase activity byquantifying the generation of the 4-methyl umbelliferone fluorescentcleavage product after addition of the methylumbelliferyl-β-D-galactoside (Sigma #M1633) substrate on amicrofluorimeter (365 nm for excitation and 450 nm for emission).Antiviral activity (IC₅₀) of the test compound is determined bycomparing the flourescence obtained in absence of compound to thatobtained in the presence of compound. Data is shown in Table I.

VZV Antiviral (ELISA) Assay

For the generation of stock VZV to be used in the assay, VZV strainEllen (ATCC #VR-1367) is used to infect human foreskin fibroblast (HFF)cells at low multiplicity (less than 0.1) and incubated overnight at 37°C. in 5% CO₂. After the overnight incubation, the mixture of uninfectedand VZV-infected HFF infected cells are then harvested and added to eachwell of 96-well plates (3.5×10⁴ cells in 100 μl DMEM supplemented with2% FBS) which contain test compound or the reference standard drugcontrol (in 100 μl DMEM supplemented with 2% FBS per well). These cellsare incubated for three days at 37° C. in 5% CO₂, then fixed for ELISAassay. The primary antibody is murine anti-VZV glycoprotein IImonoclonal antibody (Applied Biosystems, Inc. #13-145-100) and thesecondary antibody is goat anti-mouse IgG linked to β-galactosidase.Thus the extent of viral replication is determined by assessingβ-galactosidase activity by quantifying the generation of the 4-methylumbelliferone fluorescent cleavage product after addition of the methylumbelliferyl-β-D-galactoside (Sigma #M1633) substrate on amicrofluorimeter (365 nm for excitation and 450 nm for emission).Antiviral activity (IC₅₀) of the test compound is determined bycomparing the flourescence obtained in absence of compound to thatobtained in the presence of compound. Data is shown in Table I.

TABLE I % inhibition IC50 IC50 (ug/ml) 10 ug/ml (ug/ml) IC50 (ug/ml)Example HSV VZV VZV HCMV  86 >10 32 >10 0.04  88 >10 .03 0.013  90 >100.07  91 >10 6 >10 0.018 144 7 10 145 2 51 >15 >10 146 >10 14 >10 >10147 10 42 >10 >50 153 2 8 >10 >10 154 4 23 >10 10 155 5 22 >10 5 158 452 >15 >10 159 >10 62 >10 >10 160 2.5 27 >10 >10 161 3 113 5 >10 163 330 >10 7 166 9 30 >10 >10 167 10 70 3.8 9 168 3 >10 2.5 169 3 26 >10 4170 >10 32 >10 0.2 172 >10 25 >10 >10 173 >10 31 >10 0.08 174 50 8 >10 6175 2 24 >10 >10 200 >10 55 >15 0.02 201 >10 78 8 0.023 224 3.5 30 >100.8 225 1 30 >10 >10 230 >10 >10 0.015 233 >10 30 >10 0.09 236 >1040 >10 0.7 237 >10 17 >10 0.02 246 >10 37 4 0.05 249 >10 59 >10 0.4264 >10 28 >10 >10 279 >10 >10 >10 280 >10 >10 >10 281 >10 31 >10 >10288 >10 30 >10 4 323 3 45 >10 0.03 330 >10 29 >10 0.15 331 1.8 98 5 2341 2 50 >10 0.15 344 4 72 7 0.25 350 >10 50 >10 1 351 3 90 3.5 0.3 3523 51 >10 0.6 353 0.6 86 7 0.04 354 0.8 75 7 2 361 8 26 >10 0.25 365 1075 5 0.035 368 >10 20 >10 0.35 371 >10 45 >10 >10 376 3 83 7 0.8 378 >1031 >10 0.033 379 >10 27 >10 >10 391 8 97 6 0.019 396 >10 26 >10 0.7398 >10 5 >10 0.13 403 6 108 >15 0.09 406 >10 28 >10 0.12 409 >10 5 >102 411 8 99 2 0.024 413 5 103 5 0.081 416 >10 87 >15 0.25 421 8 >10 0.75422 5 69 >10 0.058 424 3 103 0.7 0.09 430 >10 >10 0.4 431 >10 >10 0.06435 10 94 0.9 0.08 436 10 >10 0.15 438 5 73 1.5 3 439 9 46 >10 0.5 440 19 0.3 441 >10 >10 0.17 445 10 >10 0.15 446 10 >10 0.7 447 >10 >10 >10449 >10 >10 1.6 450 >10 >10 0.05 451 8 >10 0.15 453 >10 3 0.07 455 >1030 >10 0.3 456 >10 12 >10 0.07 457 >10 26 >10 0.019 462 >10 6 >10 1464 >10 25 >10 0.15 466 >10 93 >10 0.011 467 >10 93 >15 0.12 468 >1050 >10 0.06 469 >10 54 >10 0.1 470 0.6 17 >10 0.7 472 >10 31 >10 0.8473 >10 40 >10 0.3 474 >10 22 >10 1 478 >10 31 >10 0.4 479 >10 30 >100.1 481 >10 32 >10 0.5 482 9 33 >10 0.3 485 >10 11 >10 0.03 486 >1022 >10 0.045 488 >10 13 >10 1.2 489 4 99 3.5 0.17 494 >10 6 >10 3.5495 >10 27 >10 3 500 >10 48 >10 0.021 501 >10 10 >10 0.032 503 8 64 >100.053 505 10 79 8 0.2 508 >10 7 >10 0.013 509 >10 31 >10 0.03 510 819 >10 0.04 513 >10 10 >10 0.011 516 >10 7 >10 0.04 521 10 97 3 0.04522 >10 32 >10 0.025 524 4 95 2 0.055 526 >10 22 2.5 3 528 3.2 107 50.25 530 5 96 6 0.15 532 >10 6 0.009 534 7 >10 0.05 535 >10 >10 0.016537 9 10 0.003 539 >10 >10 0.036 541 7 >10 0.017 542 >10 >10 0.0011544 >10 >10 0.02 545 3 7 0.012 546 1.7 7 0007 547 >10 10 0.006548 >10 >10 0.008 550 >10 >10 0.013 551 >10 >10 0.043 554 >10 1.5 0.01555 >10 4 0.008 556 >10 >7.5 0.006 557 >10 >10 0.006 558 7 >10 0.05559 >10 >10 0.012 560 >10 >10 0.008 561 >10 8 0.05 562 >10 8 0.004564 >10 5 0.027 565 >10 0.22 0.01 571 >10 0.013 572 >10 0.0078 573 >100.05 574 >10 0.089 575 2 0.017 579 6 0.05 681 >10 0.01 582 8 0.01584 >10 0.0026 585 >10 0.015 587 >10 0.005 588 >10 0.36 0.03 590 >10 10.12 592 >10 2 0.049 594 >10 >10 0.011 595 >10 3 0.022 597 >10 >10 0.008599 >10 >10 0.005 600 >10 >10 0.012 601 >10 >10 0.0011 602 >10 >100.0015 603 >10 >10 >0.5 604 >10 10 0.025 605 >10 10 0.062 606 >10 >100.0023 607 8 >10 0.09 611 >10 0.5 612 1 0.049 613 >10 0.011 614 7 0.024615 >10 0.005 617 >10 0.013 618 >10 0.0016 624 >10 0.002 626 10 >10 0.07627 10 >10 0.014 630 >10 4 0.4 631 6 6 0.15 635 10 4 0.15 637 >10 >100.014 638 >10 >10 0.01 639 >10 >10 0.07 644 >10 8 0.03 645 >10 10 0.003646 >10 2.6 0.03 647 >10 0.1 0.007 648 >10 0.01 650 >10 0.05 651 >100.03 652 >10 0.03 654 >10 0.07 655 >10 0.01 657 6 0.04 662 >10 0.03663 >10 0.01 665 5 0.02 667 8 0.03 668 >10 0.009 670 >10 0.02 671 >100.005 674 >10 0.006 675 >10 0.05 676 >10 0.013 678 >10 0.005 679 10 0.01681 >10 0.02 682 >10 0.006 683 10 0.02 684 10 0.005 685 10 0.006 686 >100.007 688 >10 0.006 689 7 0.007 690 7 0.004 691 >10 0.008 692 6 0.04693 >10 0.03 694 10 0.04 697 7 0.04 698 6 0.04 699 >10 0.016 700 >100.004 701 >10 0.008 702 4 0.01 703 >10 0.007 704 >10 0.006 705 >10 0.006706 >10 0.04 707 >10 0.005 708 >10 0.005 709 >10 0.05 710 >10 0.006711 >10 0.004 713 >10 0.009 714 >10 0.02 715 >10 0.03 716 >10 0.01717 >10 0.003 718 6 0.02 720 >10 0.01 722 >10 0.015 723 >10 0.03 726 >10728 9 729 0.02 730 0.033 7310 >10 0.007 732 0.022 733 0.018 734 >100.009 735 0.022 736 0.012 737 >10 0.005 738 >10 0.11 739 >10 0.02 7400.1 741 >10 0.02 742 >10 0.009 743 >10 0.09 745 9 0.0025 746 >10 0.005747 >10 0.002 748 >10 0.28 749 >10 0.06 750 >10 0.01 759 >10 2 >10762 >10 1.5 0.002 763 5 5 0.004 764 >10 0.004 766 >10 0.006 767 >10 10.006 768 >10 0.005 769 >10 0.04 770 >10 0.006 796 >10 >7.5 4 815 0.270.0095 816 >7.5 0.0053 818 >7.5 0.0016 820 >7.5 0.006 821 >7.5 0.005822 >7.5 0.018 824 0.17 0.014 825 >7.5 0.0013 828 >7.5 0.002 829 >7.50.002 830 >7.5 0.0003 831 >7.5 0.0011 832 >7.5 0.001 833 >7.5 0.0019834 >7.5 0.002 835 >7.5 0.005 836 >7.5 0.004 837 3.60 0.03 838 >7.50.0007 839 >7.5 0.004 840 0.14 0.0015 841 0.77 0.0011 842 1.55 0.02843 >7.5 0.0031 844 1.03 0.0008 845 >7.5 0.0060 846 1.04 0.0130 847 >7.50.0008 848 0.19 0.002 849 1.82 0.002 850 2.33 0.0008 851 1.43 0.017852 >7.5 0.005 853 0.62 0.004 854 0.02 855 0.02 856 0.02 857 >7.5 0.0006858 >7.5 0.0007 859 0.5 0.00001 860 >7.5 0.001 861 >7.5 0.002 862 >7.50.1 863 >7.5 2.0 864 >7.5 0.5 865 >7.5 0.0001 866 >10 50 >10 0.035875 >50 18 >10 >2.2 879 4 65 10 0.3 888 6 31 >10 0.06 897 >10 62 >100.037 902 >10 10 >10 0.12 904 12 58 >10 0.4 905 4 82 2 0.3 907 >1036 >10 0.009 911 >10 25 >10 0.3 912 >10 0 >10 0.16 913 >10 15 >10 0.056917 10 >10 0.2 918 >10 >10 0.03 919 >10 >10 0.05 921 8 85 7 0.05 922 >1084 7 0.01 939 >10 53 15 0.018 960 >10 58 >10 0.03 961 >10 20 >10 0.006964 >10 9 >10 0.03 965 >10 36 >10 0.008 966 >10 42 >10 0.02 969 >1040 >10 0.03 970 >10 16 >10 0.06 971 >10 9 >10 0.013 972 >10 95 >15 0.006974 >10 14 >10 0.011 979 8 88 12 0.19 980 >10 56 >10 0.05 983 >10 52 >100.12 986 >10 5 >10 0.031 989 >10 21 >10 0.016 990 8 99 4.5 0.011 991 >103 >10 0.022 992 >10 29 >10 0.018 993 >10 >10 0.013 994 >10 >10 0.07 99610 >10 0.15 998 >10 >10 0.016 1000  >10 >10 0.39 1002  >10 >10 0.071004  >10 36 >10 0.5 1005  >10 16 >10 2 1006  >10 13 >10 0.2 1007  >1018 >10 0.11 1008  >10 15 >10 0.12 1009  10 22 >10 0.2 1011  >10 20 >100.039 1018  >10 2 >10 0.4 1019  >10 2 >10 1.5 1021  8 68 >10 0.0941126  >10 0.7 5.8 1127  9.5 3.7 1 1128  >10 >10 1.3 1129  1.9 >10 11130  2 5.5 2 1131  2.2 9 1.5 1132  2.6 3.9 1.2 1133  6 >10 1.5 1134 2.4 1.6 1 1135  3.6 7.5 1.3 1136  2.9 5 1.6 1137  >10 3.5 0.61138  >10 >10 0.65 1139  3.7 6 1.2 1140  3.5 4 1.6 1141  >10 >10 1.91142  >10 >10 1.8 1143  >10 >10 7.5

Thus, compounds of the present invention are potent inhibitors of thegrowth and replication of the herpes viruses, including HCMV, VZV andHSV, effectively inhibiting viral yield.

In accordance with the present invention, compounds of the presentinvention may be administered to a patient suffering from a herpesvirus, including HCMV, VZV and HSV in an amount effective to inhibit thevirus. Compounds of the present invention are thus useful to ameliorateor eliminate the symptoms of the herpes virus infections in mammalsincluding, but not limited to humans.

Compounds of the invention may be administered to a patient either neator with a convention pharmaceutical carrier.

Applicable solid carriers can include one or more substances which mayalso act as flavoring agents, lubricants, solubilizers, suspendingagents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

The therapeutically effective dosage to be used in the treatment ofherpes virus infection must be subjectively determined by the attendingphysician. The variables involved include the condition, age and weightof the patient. The novel method of the invention for treating herpesvirus infection comprises administering to a subject, including humans,an effective amount of at least one compound of Formula 1 or anon-toxic, pharmaceutically acceptable salt thereof. The compounds maybe administered orally, rectally, parenterally or topically to the skinand mucosa. The usual daily dose is depending on the specific compound,method of treatment and condition of the patient. The usual daily doseis 0.01-1000 mg/Kg for oral application, preferably 0.5-500 mg/Kg, and0.1-100 mg/Kg for parenteral application, preferably 0.5-50 mg/Kg.

What is claimed:
 1. A compound having the formula:

wherein R₁-R₅ are independently selected from hydrogen, alkyl of 1 to 6carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbonatoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbonatoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl,halogen, —CN, —NO₂, —CO₂R₆, —COR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, —CONR₇R₈,—NR₆N(R₇R₈), —N(R₇R₈) or W—Y—(CH₂)_(n)—Z provided that at least one ofR₁-R₅ is not hydrogen; or R₂ and R₃ or R₃ and R₄, taken together form a3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R₆ andR₇ are independently hydrogen, alkyl of 1 to 6 carbon atoms,perhaloalkyl of 1 to 6 carbon atoms, or aryl; R₈ is hydrogen, alkyl of 1to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl orheteroaryl, or R₇ and R₈, taken together may form a 3 to 7 memberedheterocycloalkyl; W is O, NR₆, or is absent; Y is —(CO)— or —(CO₂)—, oris absent; Z is alkyl of 1 to 4 carbon atoms, —CN, —CO₂R₆, COR₆,—CONR₇R₈, —OCOR₆, —NR₆COR₇, —OCONR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆,SR₆N(R₇R₈), —N(R₇R₈) or phenyl; G is thiazole; X is a bond, —NH, alkylof 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6carbon atoms, or thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6.2. A compound of claim 1 wherein R₁ through R₅ are independently,hydrogen alkyl of 1 to 6 carbon atoms, halogen, perhaloalkyl of 1 to 6carbon atoms, OR₆ or N(R₇R₈).
 3. A compound of claim 1 wherein R₁, R₂and R₃ are hydrogen and R₄ and R₅ are independently, halogen or CF₃. 4.A compound of claim 1 wherein R₁, R₂ and R₄ are hydrogen and R₃ and R₅are independently, halogen or CF₃.
 5. A compound of claim 1 wherein X isa bond.
 6. A compound of claim 1 wherein X is straight chain alkyl.
 7. Acompound of claim 1 wherein X is alkyl of 1 to 4 carbon atoms.
 8. Acompound of claim 1 wherein X is CH(J) and J is alkyl of 1 to 6 carbonatoms.
 9. A compound of claim 8 wherein J is methyl.
 10. A compound ofclaim 1 wherein X is CH(J) and G is thiazolyl.
 11. A compound which isThiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-PHENYL}-amide; or apharmaceutical salt thereof.
 12. A pharmaceutical composition comprisinga compound of the formula:

wherein R₁-R₅ are independently selected from hydrogen, alkyl of 1 to 6carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbonatoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbonatoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl,halogen, —CN, —NO₂, —CO₂R₆, —COR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, —CONR₇R₈,—NR₆N(R₇R₈), —N(R₇R₈) or W—Y—(CH₂)_(n)—Z provided that at least one ofR₁-R₅ is not hydrogen; or R₂ and R₃ or R₃ and R₄, taken together form a3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R₆ andR₇ are independently hydrogen, alkyl of 1 to 6 carbon atoms,perhaloalkyl of 1 to 6 carbon atoms, or aryl; R₈ is hydrogen, alkyl of 1to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl orheteroaryl, or R₇ and R₈, taken together may form a 3 to 7 memberedheterocycloalkyl; W is O, NR₆, or is absent; Y is —(CO)— or —(CO₂)—, oris absent; Z is alkyl of 1 to 4 carbon atoms, —CN, —CO₂R₆, COR₆,—CONR₇R₈, —OCOR₆, —NR₆COR₇, —OCONR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆,SR₆N(R₇R₈), —N(R₇R₈) or phenyl; G is thiazole; X is a bond, —NH, alkylof 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6carbon atoms, or thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6,or a pharmaceutical salt thereof, and a pharmaceutically acceptablecarrier or diluent.
 13. A method of inhibiting the replication of aherpes virus in a mammal comprising contacting a compound of theformula:

wherein R₁-R₅ are independently selected from hydrogen, alkyl of 1 to 6carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbonatoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbonatoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl,halogen, —CN, —NO₂, —CO₂R₆, —COR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, —CONR₇R₈,—NR₆N(R₇R₈), —N(R₇R₈) or W—Y—(CH₂)_(n)—Z provided that at least one ofR₁-R₅ is not hydrogen; or R₂ and R₃ or R₃ and R₄, taken together form a3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R₆ andR₇ are independently hydrogen, alkyl of 1 to 6 carbon atoms,perhaloalkyl of 1 to 6 carbon atoms, or aryl; R₈ is hydrogen, alkyl of 1to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl orheteroaryl, or R₇ and R₈, taken together may form a 3 to 7 memberedheterocycloalkyl; W is O, NR₆, or is absent; Y is —(CO)— or —(CO₂)—, oris absent; Z is alkyl of 1 to 4 carbon atoms, —CN, —CO₂R₆, COR₆,—CONR₇R₈, —OCOR₆, —NR₆COR₇, —OCONR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆,SR6N(R7R8), —N(R₇R₈) or phenyl; G is thiazole; X is a bond, —NH, alkylof 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6carbon atoms, or thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6,or a pharmaceutical salt thereof, with a herpes virus.
 14. The method ofclaim 13 wherein the herpes virus is human cytomegalovirus.
 15. Themethod of claim 13 wherein the herpes virus is varicella zoster virus.16. The method of claim 15 wherein the compound is substantially pure(S) optical isomer.
 17. The method of claim 13 wherein the herpes virusis herpes simplex virus.
 18. A method of treating a patient sufferingfrom a herpes virus infection comprising administering to the patient atherapeutically effective amount of a compound having the formula:

wherein R₁-R₅ are independently selected from hydrogen, alkyl of 1 to 6carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbonatoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbonatoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl,halogen, —CN, —NO₂, —CO₂R₆, —COR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆, —CONR₇R₈,—NR₆N(R₇R₈), —N(R₇R₈) or W—Y—(CH₂)_(n)—Z provided that at least one ofR₁-R₅ is not hydrogen; or R₂ and R₃ or R₃ and R₄, taken together form a3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R₆ andR₇ are independently hydrogen, alkyl of 1 to 6 carbon atoms,perhaloalkyl of 1 to 6 carbon atoms, or aryl; R₈ is hydrogen, alkyl of 1to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl orheteroaryl, or R₇ and R₈, taken together may form a 3 to 7 memberedheterocycloalkyl; W is O, NR₆, or is absent; Y is —(CO)— or —(CO₂)—, oris absent; Z is alkyl of 1 to 4 carbon atoms, —CN, —CO₂R₆, COR₆,—CONR₇R₈, —OCOR₆, —NR₆COR₇, —OCONR₆, —OR₆, —SR₆, —SOR₆, —SO₂R₆,SR6N(R7R8), —N(R₇R₈) or phenyl; G is thiazole; X is a bond, —NH, alkylof 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6carbon atoms, or thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6;or a pharmaceutical salt thereof.
 19. The method of claim 18 wherein theherpes virus is human cytomegalovirus.
 20. The method of claim 18wherein the herpes virus is varicella zoster virus.
 21. The method ofclaim 20 wherein the compound is substantially pure (S) isomer.
 22. Themethod of claim 18 wherein the herpes virus is herpes simplex virus. 23.A compound of claim 1 selected from Thiazole-4-carboxylic acid{4-[3-(4-tert-butyl-benzyl)-thioureido]-phenyl}-amide,Thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}-amide,Thiazole-4-carboxylic acid{4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide,Thiazole-4-carboxylic acid{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-amide,Thiazole-4-carboxylic acid{4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide,Thiazole-4-carboxylic acid{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,Thiazole-4-carboxylic acid{4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide,Thiazole-4-carboxylic acid(4-{3-[1-(4-bromo-phenyl)-ethyl]-thioureido}-phenyl)-amide,N-(4-{[({1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,N-(4-{[({1-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,N-(4-{[({1-[2-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,N-(4-{[({1-[2,4-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,N-{4-[({[1-(2,4-dimethylphenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-{4-[({[1-(2,4-dichlorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-{4-[({[1-(3-methylphenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-(4-{[({1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,N-{4-[({[1-(2-chloro-4-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-{4-[({[1-(3,4-difluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-{4-[({[1-(4-bromo-2-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-{4-[({[1-(3-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-{4-[({[1-(2-bromophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-{4-[({[1-(3-bromophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-(4-{[({1-[2-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,N-{4-[({[1-(2,4-difluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-(4-{[({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,N-(4-{[({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,N-{4-[({[1-(3,4-dichlorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-(4-{[({1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,N-(4-{[({1-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,N-{4-[({[1-(4-chloro-2-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-(4-{[({1-[4-fluoro-2-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,N-{4-[({[1-(4-chloro-3-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamideN-{4-[({[1-(2-bromo-4-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-{4-[({[1-(3,4-dibromophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,N-{4-[({[1-(3-chloro-4-fluorophenyl)ethyl]amino}carbothioyl)amino]phenyl}-1,3-thiazole-4-carboxamide,andN-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide;or a pharmaceutical salt thereof.
 24. A compound which isN-(4-{[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}phenyl)-1,3-thiazole-4-carboxamide,or a pharmaceutical salt thereof.